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MATERIA  MEDICAiPHARMA- 
COLOGY  :  THERAPEUTICS 
PRESCRIPTION  WRITING 

FOR  STUDENTS  AND  PRACTITIONERS 


BY 

WALTER  A.  BASTEDO,  Ph.G.,  M.D. 

Assistant  Professor    of  Clinical    Medicine,    Columbia   University; 
Associate  Attending  Physician, St.  Luke's  Hospital,  New  York: 
Attending  Physician,  City  Hospital,  New  York;  Consulting 
Physician,  St.  Vincent's  Hospital.  Staten  Island;    Con- 
sulting Gastro-enterologist,  Staten  Island  Hospital; 
Fifth    Vice-President,  United    States    Pharma- 
copoeial  Convention;    formerly  Curator    of 
the    New    York    Botanical    Garden 


SECOND  EDITION,  FiESET 


PHILADELPHIA    AND    LONDON 

W.  B.  SAUNDERS  COMPANY 

1918 


If 


Copyright,    1913,    by  W.  B.  Saunders     Company. 

Reprinted  February,  1914,  May,  1914,  May,  1915, 

and  September,  1916.      Revised,  entirely 

reset,  reprinted,  and  recopyrighted 

January,  1918 


Copyright,  1918,  by  W.  B.  Saunders  Company 


Reprinted  May,  1918 


THE     USE      IN     THIS      VOLUME     OF     CERTAIN      PORTIONS     OF     T  H  E~ 


THE    UNITED  STATES   PHARMACOPOEIA!.  CONVENTI 


PRINTED    IN    AMERICA 

PRESS     OF 

W.     B.      SAUNDERS     COMPANY 
PHILADELPHIA 


TW 

121 


DEDICATED  TO 
professor  ^enrp  $)ur&  Kusfap, 

3OTANIST,    PHARMACOGNOSIST,   AND  DEAN  OF  THE   FACULTY  OF  THE   NEW  YORE 
COLLEGE  OF  PHARMACY  (COLUMBIA  UNIVERSITY) 

Dear  Doctor  Rusby: 

Will  you  do  me  the  honor  to  accept  this  dedication  as  a  token  of  ap- 
preciation of  your  high  ideals  and  of  your  indefatigable  efforts  in  the 
cause  of  pure  drugs,  and  as  an  expression  of  my  great  personal  debt  to 
you,  my  earliest  and  latest  preceptor  in  the  field  of  "materia  medica"? 

Sincerely  yours, 

WALTER  A.  BASTEDO 


PREFACE  TO   THE  SECOND   EDITION 


IN  addition  to  bringing  the  book  into  conformity  with  the 
Ninth  Revision  of  the  U.  S.  Pharmacopoeia,  there  has  been  a 
thorough  revision  throughout.  The  sections  on  alkalies,  pitu- 
itary, salvarsan,  bichloride  poisoning,  emetine,  oxygen,  and 
ergot  have  been  rewritten,  and  new  articles  have  been  intro- 
duced on  benzine  and  gasoline,  benzol,  kaolin,  fullers'  earth, 
glucose,  papaverine,  ethylhydrocupreine,  phenylcinchoninic  acid, 
magnesium  sulphate,  oil  of  chenopodium,  and  the  Dakin-Car- 
rel  antiseptic  treatment  for  wounds. 

Because  of  its  universal  use  in  medical  literature  the  term 
cubic  centimeter  (c.c.)  has  been  retained,  though,  the  U.  S.  and 
British  Pharmacopoeias  have  substituted  the  term  milliliter 
(mil.).  A  milliliter  differs  from  a  cubic  centimeter  by  such  a 
small  fraction  that  it  is  quite  negligible. 

W.  A.  BASTEDO. 

57  WEST  58™  ST.,  NEW  YORK,  N.  Y. 


PREFACE 


This  book  is  an  adaptation,  for  the  most  part,  of  lectures 
delivered  at  Columbia  University.  In  its  preparation  I  have 
kept  in  mind  that  the  physician's  reason  for  the  study  of  remedies 
is  the  "treatment  of  the  sick";  and  I  have  laid  most  stress  upon 
those  things  that  bear  on  practice,  even  to  the  exclusion  of  some 
matters  of  great  interest  in  pharmacology. 

But  I  have  endeavored  throughout  to  emphasize  the  value 
of  research,  both  in  the  laboratory  and  at  the  bedside,  and  to 
point  out  any  discrepancy  between  the  value  of  a  remedy  as. 
established  by  research  and  its  supposed  value  in  therapeutics. 
For  I  recognize  that,  as  the  result  of  research,  many  of  the 
hitherto  highly  valued  drugs  are  falling  into  merited  disuse;  and 
that  some  that  were  of  little  value  because  of  a  wrong  under- 
standing of  their  action  have  come  to  have  a  definite  place  in 
our  therapeutic  armamentarium.  Indeed,  I  have  given  place  to 
many  remedies  which  I  do  not  recommend,  but  mention  only  to 
condemn. 

I  believe  that,  as  the  outcome  of  critical  laboratory  research 
and  the  adoption  of  laboratory  methods  in  clinical  research,  we 
are  at  the  dawn  of  a  new  era  of  simple  and  practical  therapeutics, 
an  era  in  which  knowledge  will  supplant  credulity  on  the  one 
hand,  and  skepticism  on  the  other,  and  in  which  fewer  drugs  will 
be  used  but  better  treatment  given. 

Both  because  of  the  importance  of  digitalis  as  a  drug,  and 
because  of  the  recent  great  changes  in  our  knowledge  of  cardiac 
physiology  and  therapeutics,  I  have  discussed  digitalis  at  greater 
length  than  other  drugs;  and  have  drawn  my  conception  of  its 
action  as  much  from  recent  clinical  studies  (my  own  and  those 
of  other  investigators)  as  from  those  of  the  pharmacologic  labor- 
atory. In  the  chapter  on  Prescription-writing  I  have  adopted 
one  method  for  the  students  to  learn;  and  to  avoid  confusion 
have  omitted  mention  of  other  methods,  without  any  intention 
to  imply  that  they  are  inferior. 

Recognizing  that  in  a  subject  which  derives  so  much  from 
research  in  all  the  branches  of  medicine  it  would  be  impossible 
for  one  person  to  be  equally  familiar  with  all  parts,  I  have  drawn 
freely  on  the  published  researches  in  chemistry,  pharmacology, 


12  PREFACE 

physiology,  bacteriology,  and  clinical  medicine.  But  I  have  felt 
that  citation  of  authors  is,  in  the  main,  impracticable  in  a  work 
of  this  character;  so  for  the  most  part  have  omitted  credit  unless 
this  was  required  for  authority.  Likewise,  I  have  made  no  attempt 
to  compile  extensive  bibliographies.  However,  I  should  like  espe- 
cially to  mention  the  works  on  pharmacology  by  Cushny,  Soll- 
mann,  Schmiedeberg,  Heinz,  and  Meyer  and  Gottlieb;  those  on 
physiology  by  Howell,  Starling,  Schafer,  and  Leonard  Hill;  the 
sundry  publications  of  von  Noorden,  Mackenzie,  Pawlow,  Herter, 
Lee,  Lusk,  Meltzer,  Hatcher,  Hertz,  and  others;  and  the  Herter 
and  Harvey  Society  lectures. 

For  the  use  of  a  number  of  tracings  I  owe  my  deepest  thanks 
to  my  colleague,  Dr.  Charles  C.  Lieb,  whose  care  about  the  de- 
tails of  an  experiment  and  accuracy  in  recording  results  I  believe 
to  be  unsurpassed. 

W.  A.  BASTEDO. 

57  WEST  sSTH  ST.,  NEW  YORK,  N.  Y. 


CONTENTS 


PART  I 

PAGE 

INTRODUCTION 17 

THE  CONSTITUENTS  OF  ORGANIC  DRUGS 19 

PHARMACEUTIC  PREPARATIONS 37 

Definition  of  the  Kinds  in  Common  Use 39 

WEIGHTS  AND  MEASURES 43 

ACTIVE  PRINCIPLES  AND  ASSAY  PROCESSES 44 

THE  PHARMACOPOEIA 45 

DOSAGE 47 

Factors  which  Modify  the  Dose 48 

ADMINISTRATION 52 

The  Ways   in  which  Drugs  May  be  Administered  for  Systemic  and 

Remote  Local  Effect 53 

The  Time  of  Administration 56 

Sites  and  Modes  of  Action  of  Drugs 56 

Synergists  and  Antagonists 57 

SCIENTIFIC  AND  EMPIRIC  THERAPEUTICS — ANIMAL  EXPERIMENTATION 58 

THE  SCOPE  OF  TREATMENT 60 

How  MUCH  SHALL  WE  LEARN  ABOUT  DRUGS? 61 

The  Pharmacologic  Action 63 


PART  II 

INDIVIDUAL  REMEDIES 

PROTECTIVES 67 

SWEETENING  AGENTS 68 

NUTRIENTS 68 

COUNTERIRRITANTS 72 

CAUSTICS  (ESCHAROTICS) 78 

THE  DIGESTIVE  FERMENTS 81 

THE  INORGANIC  ACIDS 86 

THE  ORGANIC  ACIDS 88 

Fruit  Acids 90 

ANTACIDS 91 

Antacids  of  Alkaline  Reaction 91 

Antacids  Not  of  Alkaline  Reaction 101 

CARMINATIVES 102 

BITTERS 107 

ANTI-BITTERS 109 

CHARCOAL 109 

KAOLIN — FULLERS'  EARTH no 

EMETICS in 

ANTEMETICS 112 


14  CONTENTS 

PAGE 

ASTRINGENTS 113 

ANTHELMINTICS 115 

CATHARTICS 119 

Cathartic  Measures 122 

Cathartics  Acting  by  Selective  Affinity 1 24 

Mechanical  Agents  to  Give  Bulk  and  Soft  Consistency  to  the  Feces 1 24 

Irritants 126 

Bile  and  Bile  Salts 126 

Fixed  Oils,  Soaps,  and  Glycerin 127 

Cathartic  Mercurials 1 29 

Anthracene  Derivatives 131 

Drastics 135 

Saline  Cathartics 137 

Rectal  Treatment 143 

ANTI-DIARRHEICS 146 

MINERAL  WATERS 146 

REMEDIES  WHOSE  CHIEF  ACTION  is  UPON  THE  CIRCULATION 148 

The  Physiology  of  the  Circulation 148 

General  Circulatory  Stimulants 157 

Mechanical  Measures  for  Raising  Arterial  Pressure 225 

Measures  for  Increasing  the  Volume  of  the  Blood 225 

Remedies  Which  Lower  Blood-pressure 231 

Cardiac  Depressants : 231 

Arterial   Dilators 239 

Measures  for  Decreasing  the  Volume  of  the  Blood 245 

Shock  and  Collapse 248 

REMEDIES  WHOSE  CHIEF  ACTION  is  UPON  THE  CENTRAL  NERVOUS  SYSTEM  ..  252 

Central  Nervous  Stimulants 252 

Remedies  Which  Depress  the  Central  Nervous  System — Narcotics 282 

General  Anesthetics 282 

— Intoxicants 316 

Hypnotics 356 

Antihysterics  (Antispasmodics) 393 

DRUGS  WHICH  CHIEFLY  AFFECT  THE  PERIPHERAL  NERVOUS  SYSTEM 394 

Peripheral  Depressants 394 

Peripheral  Stimulants 436 

ANHIDROTICS 411 

DIAPHORETICS 443 

DIURETICS 450 

ANTIPYRETICS 461 

Analgesic  Antipyretics 462 

Anti-malarial  Antipyretics 470 

Antirheumatic  Antipyretics 480 

DISINFECTANTS  AND  ANTISEPTICS 488 

THERAPEUTIC  CLASSIFICATION  OF  DISINFECTANTS 514 

General  Disinfectants  and  Deodorizers 514 

Preservatives 515 

Disinfectants  for  Surgical  Supplies 515 

Disinfectants  for  Local  Use  About  Body 516 

Disinfectants  to  be  Given  by  Mouth 517 

HEAVY  METALS 517 

PHOSPHORUS 553 

IODIDES 555 

THYROID  (.LAND 560 

ANTITHYKOID  PREPARATIONS 562 

EXPECTORANTS 563 

EMMENAGOGUES 567 


CONTENTS  15 


PAGE 


CARBON  MONOXIDE 574 

BENZINE  AND  GASOLINE 576 

BENZOL 577 

OXYGEN 578 

PART  III 

PRESCRIPTION  WRITING 

LIQUID  PRESCRIPTIONS 583 

ADMINISTRATION  OF  LIQUIDS 585 

ADMINISTRATION  OF  SOLIDS 586 

LATIN 587 

THE  FORM  OF  A  PRESCRIPTION 591 

FIGURING  THE  QUANTITIES 593 

ABBREVIATIONS 597 

PRACTICE  IN  BULK  PRESCRIPTIONS 599 

PRACTICE  IN  PRESCRIPTIONS  FOR  OBJECTS  TO  BE  COUNTED 601 

INCOMPATIBILITY 603 

INDEX. 607 


MATERIA    MEDICA, 
PHARMACOLOGY,    THERAPEUTICS, 
AND    PRESCRIPTION-WRITING 


PART  I 
INTRODUCTION 

"Medicine  sometimes  cures,  it  often  relieves,  it  always  consoles." 

THE  physician's  calling  has  arisen  from  the  needs  of  the  sick, 
a  person  who  is  ill  desiring  the  services  of  some  one  who  can 
help  him  to  get  well.  If  the  sick  man  cannot  be  made  well, 
he  wants  as  much  improvement  in  his  health  as  possible,  so  that 
he  may  do  things;  for  example,  attend  to  his  business,  or  at 
least  get  about.  If  his  health  cannot  be  improved,  he  wants  his 
comfort  promoted  and  his  life  prolonged.  Thus  the  objects 
of  the  practice  of  medicine  are:  to  prolong  life,  to  secure  comfort, 
to  improve  health,  or  to  promote  recovery. 

The  physician  accomplishes  these  objects  by  doing  something 
for  his  patients,  i.  e.,  by  treating  them.  Therefore  his  ability 
to  treat  his  patients  successfully  is  what  constitutes  his  direct 
personal  value  for  them,  and  is  the  ultimate  raison  d'etre  of  the 
physician's  calling.  Hence  the  importance  of  a  familiarity  with 
the  available  means  of  treatment,  i.  e.,  with  remedial  or  thera- 
peutic measures. 

Therapeutics  is  the  science  of  the  use  of  remedial  measures. 
When  a  physician  orders  a  patient  to  bed,  he  employs  a  thera- 
peutic measure.  Also  when  he  orders  a  cold  bath,  a  cathartic, 
or  the  application  of  a  mustard  plaster;  or  when  he  applies  a 
splint  to  a  broken  arm,  or  removes  an  inflamed  appendix,  or  sits 
by  the  bed  and  calms  a  nervous  patient. 

Preventive  medicine  goes  a  step  further  than  remedial  medicine, 
in  that  it  designs  to  prevent  the  appearance  or  spread  of  disease. 

The  main  therapeutic  and  preventive  measures  may  be 
grouped  as  follows: 

i.  Hygienic — those  which  have  to  do  with  cleanliness,  dis- 
infection, the  prevention  of  the  spread  of  contagion,  ventilation, 
the  selection  of  a  patient's  bedroom,  care  of  bedding,  clothing, 
etc. 

2  I7 


l8  PHARMACOLOGY  AND   THERAPEUTICS 

2.  Mechanical — the  use  of  bandages,  splints,  ligatures,  cath- 
eterization  to  empty  the  bladder,  massage,  gymnastics,  etc. 

j.  Operative — the  performance  of  surgical  and  obstetric  oper- 
ations. 

4.  Physical — the  use  of  physical  agents:  heat,  cold,  light, 
electricity,  £-rays,  radium,  etc. 

5.  Hydrotherapeutic — the  external  use  of  water  and  its  modi- 
fications: ice,  cold  water,  hot  water,  and  steam,  in  the  form  of 
baths,  packs,  douches,  etc. 

6.  Dietetic — the  modifications  of  diet  for  the  sick. 

7.  Suggestive    or    psychotJierapeutic — suggestion,    hypnotism, 
mental  buoying,  etc.     The  psychic  influence  of  a  physician  is 
of  great  importance,  and  to  reassure  a  patient  when  she  is  fearing 
the  worst,  to  encourage,  to  stimulate  the  energies  and  the  will, 
are  among  the  functions  of  the  physician  and  are  therapeutic 
measures. 

8.  Pharmaceutic — the  use  of  pharmaceutic  or  drug  remedies. 
Materia  Medica. — Drug  remedies  are  known  collectively  as 

the  "materia  medica,"  or  medical  materials.  The  science  which 
deals  with  the  properties  of  drugs  is  called  materia  medica  or, 
more  correctly,  pharmacology.  It  is  a  term  that  is  employed  in 
a  broad  sense  to  include  everything  relating  to  drugs. 

In  connection  with  drugs,  there  are  several  great  fields  of 
work,  the  most  important  being: 

/.  Pharmacognosy — the  study  of  the  physical  properties  of 
crude  drugs.  The  pharmacognosist  studies  the  methods  by  which 
drugs  are  collected,  their  appearance  on  the  market,  the  char- 
acters by  which  they  may  be  identified  and  their  quality  esti- 
mated, their  adulterants  in  the  whole  and  in  the  powdered  state, 
etc. 

2.  Pharmacy — the  art  of  preparing  drugs  for  use.  Manu- 
facturing pharmacy  is  the  art  of  manufacturing  drugs  into  forms 
suitable  for  use  in  medicine.  Dispensing  pharmacy  is  the  art  of 
making  up  prescriptions.  The  pharmacist  makes  his  knowledge 
tell  on  the  manufacture  of  preparations  and  their  combination 
into  prescriptions.  He  studies  weights  and  measures,  solubilities, 
incompatibilities,  keeping  qualities,  chemic  reactions,  the  extrac- 
tion of  active  principles,  and  the  making  of  preparations  suitable 
for  use  in  the  practice  of  medicine. 

j.  Pharmaceutic  chemistry — the  study  of  the  chemistry  of 
drugs  and  preparations  of  drugs. 

./.   Pharmacodynamics  or  pharmacology  (in  its  restricted  sense) 

the  study  of  the  action  of  drugs.    .The  pharmacologist  studies 

the  action  of  drugs  on  the  tissues  and  structures  of  living  things. 

The  practicing  physician  does  not  require  a  knowledge  of 


INTRODUCTION  19 

pharmacognosy,  and  he  needs  only  such  knowledge  of  pharmacy 
as  may  prove  helpful  to  him  in  prescribing  the  drugs  he  desires 
his  patient  to  have.  But  his  knowledge  of  pharmacology  should 
be  extensive. 

Drugs  are  either:  (i)  Pure  chemicals,  such  as  sodium  bicar- 
bonate or  potassium  iodide;  (2)  mixed  mineral  products,  such  as 
petroleum  oil,  vaseline,  or  ichthyol;  or  (3)  certain  animal  or  plant 
parts  or  products.  Of  animal  nature  or  origin  are  musk,  canthar- 
ides,  adrenaline,  lard,  honey;  and  of  plant  nature  or  origin  are 
herbs,  barks,  roots,  leaves,  fruits,  seeds,  resins,  alkaloids,  etc. 

"Crude  drugs"  are  the  commercial  forms  of  the  natural  animal 
or  plant  drugs  as  they  are  brought  to  the  market.  Their  em- 
ployment in  medicine  is  due  to  the  fact  that  they  contain  or 
yield  more  or  less  definite  chemic  bodies  of  medicinal  value. 
These  bodies  are  known  as  the  "active  constituents."  In  some 
cases  these  constituents  are  found  in  all  parts  of  a  plant,  so  that 
the  whole  plant  is  marketed  as  the  crude  drug;  but  mostly  they 
occur  in  one  part  only,  such  as  the  leaf  or  root,  or  are  stored  in 
greatest  abundance  in  one  part,  so  that  that  part  is  selected  for 
the  market  and  is  the  crude  drug.  Sometimes,  as  in  the  case  of 
asafetida,  an  exudate  contains  the  active  constituents  and  is  the 
crude  drug,  no  structural  part  of  the  plant  being  marketed  at  all. 
The  crude  drug  of  digitalis  is  the  dry  leaf,  the  leaf  of  the  digitalis 
plant  being  the  chief  depository  of  the  peculiar  constituents  on 
which  digitalis  depends  for  its  medicinal  activity;  the  crude  drug 
of  rhubarb  is  the  dried  root;  of  peppermint,  the  leaves  and  flower- 
ing tops;  of  cascara,  the  bark;  of  opium,  the  dried  milk  juice;  of 
Spanish  fly,  the  whole  dried  insect. 

THE   CONSTITUENTS   OF   ORGANIC   DRUGS 

These  may  be  classified  into:  i.  The  Active  Constituents. 
2.  The  Inert  Constituents. 

The  latter  are  the  cellulose,  wood,  and  other  structural  parts 
of  the  drug,  and  in  some  instances  starch,  albumen,  fat,  wax, 
coloring-matter,  and  other  substances  which  have  no  distinct 
pharmacologic  action,  though  their  presence  in  a  preparation 
may  have  a  modifying  effect  on  the  absorbability  and  activity 
of  the  active  pharmacologic  constituents. 

The  active  constituents  may  be  active  in  two  different  ways, 
viz.:  pharmacologically  active,  i.  e.,  having  an  action  on  living 
animal  tissues,  and  pharmaceutically  active,  i.  e.,  capable  of  causing 
precipitation  or  otherwise  notable  chemic  changes  in  a  prescrip- 
tion or  preparation.  Both  kinds  are  found  in  cinchona  bark, 
which  contains  not  only  quinine  and  other  alkaloids  upon  which 


20  PHARMACOLOGY   AND   THERAPEUTICS 

its  pharmacologic  activity  depends,  but  also  tannic  acid,  an 
astringent  drug.  In  an  ordinary  dose  of  cinchona  the  tannic 
acid  is  too  little  in  amount  to  have  any  important  astringent 
effect,  and  is,  therefore,  not  pharmacologically  active;  yet  if 
the  cinchona  preparation  is  mixed  with  a  preparation  of  iron, 
the  tannic  acid  becomes  pharmaceutically  active  and  changes 
the  iron  salt  into  ink.  Again,  the  pharmacologically  active 
principles  of  digitalis  are  not  readily  soluble  in  water,  so  an 
aqueous  preparation,  such  as  the  infusion,  would  not  represent 
the  activity  of  digitalis  were  it  not  for  the  fact  that  digitalis  also 
contains  a  body  which  possesses  the  peculiar  property  of  rendering 
the  active  medicinal  principles  soluble  in  water.  This  body 
(digitonin)  is,  therefore,  pharmaceutically  active,  and  as  such 
is  important. 

A  constituent  is  called  an  active  principle  when  to  it  may  be 
attributed,  either  wholly  or  in  part,  the  physiologic  action  of  the 
drug. 

The  active  constituents  of  organic  drugs  may  be  either: 

a.  Single   chemic   bodies,   or — 

b.  Mixtures  of  such  a  nature  that  separation  into  their  com- 
ponents is  not  advantageous. 

The  classes  of  active  constituents  are: 

A.  The  Single  Chemicals. 

1.  Plant  acids  and  their  salts. 

2.  Alkaloids. 

3.  Neutral  principles. 

4.  Toxalbumins. 

5.  Ferments. 

6.  Sugars,  starches,  and  gums. 

7.  Tannins. 

B.  The  Mixtures. 

1.  Fixed  oils,  fats,  and  waxes. 

2.  Volatile  oils. 

3.  Resins. 

4.  Oleoresins. 

5.  Gum-resin^. 

6.  Balsams. 

The  last  three  are  natural  exudations  from  plants. 

1.  Plant  Acids  and  Their  Salts.     The  citric  acid  of  lemons, 
the  tartaric  acid  of  grapes,  benzoic,  cinnamic,  salicylic,  tannic 
acid,  and  some  of  their  salts  are  of  interest  pharmacologically. 
Glycyrrhizin,  the  sweet  principle  of  glycyrrhiza  (licorice),  is  really 
glycyrrhizic  acid,  and  is  sweet  to  the  taste  only  in  the  form  of 
alkaline  salts.    It  is  precipitated  and  rendered  tasteless  by  acids. 

2.  Alkaloids. — -These  are  a  class  of  organic  bodies  of  alkaline 


THE   CONSTITUENTS   OF   ORGANIC   DRUGS  21 

reaction,  composed  of  carbon,  hydrogen,  and  nitrogen,  and  some- 
times other  elements.  The  class  includes  a  great  many  of  our 
most  powerful  drugs.  Their  basic  or  alkaline  nature  gives  the 
name  alkaloid  (alkali  and  eidos,  resembling).  They  possess  the 
power  of  neutralizing  acids  with  the  formation  of  salts,  and  in 
doing  so  take  up  the  acid  without  the  liberation  of  hydrogen. 
In  this  respect  they  resemble  ammonia,  and  differ  from  the  alkali 
metals. 

Na  +  HC1  =  NaCl  +  H. 
NH3  4-  HC1  =  NH3.HC1 
2  (strychnine)  +  HC1  =  C^H^ 


Some  of  the  alkaloids  are  strongly  basic,  while  others,  such 
as  caffeine,  are  so  feebly  basic  that  they  are  with  difficulty  made 
to  form  salts  at  all.  Most  are  monacid,  uniting  one  molecule 
of  the  alkaloid  for  each  basic  hydrogen  in  the  acid.  A  few  are 
diacid.  Quinine  forms  two  different  salts  with  acid,  those  with 
sulphuric  acid,  for  example,  being  quinine  sulphate,  the  neutral 
sulphate,  in  which  two  molecules  of  quinine  unite  with  one  mole- 
cule of  the  dibasic  sulphuric  acid,  (020^24X202)2.  H^SC^-f-yH^O, 
and  quinine  bisulphate,  the  acid  sulphate,  in  which  only  one 
molecule  of  quinine  unites  with  each  molecule  of  sulphuric  acid, 
C2oH24N2O2.H2SO.i+7H2O.  The  uncombined  alkaloids,  to  dis- 
tinguish them  from  the  "alkaloidal  salts,"  are  known  as  "pure 
alkaloids,"  and  are  not  much  employed. 

Nomenclature.  —  To  distinguish  these  basic  substances  from 
the  neutral  principles,  the  United  States  Pharmacopoeia  makes 
all  the  names  of  alkaloids  end  in  ine  (Latin,  ina),  as  quinine 
(quinina),  cocaine  (cocaina);  and  the  names  of  the  neutral  prin- 
ciples end  in  in  (Latin,  inum),  as  digitalin  (digitalinum),  salicin 
(salicinum).  This  is  a  simple  device  for  distinction,  and  it  serves 
a  good  purpose.  It  is  to  be  regretted  that  this  distinctive  spelling 
is  not  followed  in  all  the  text-books.  The  old  form,  ending  in  ia, 
as  quinia,  morphia,  strychnia,  is  now  obsolete. 

Solubility.  —  The  pure  alkaloids  are,  as  a  rule,  not  readily 
soluble  in  water,  but  they  dissolve  more  or  less  readily  in  alcohol, 
ether,  chloroform,  and  the  fixed  and  volatile  oils.  The  alkaloidal 
salts,  on  the  contrary,  are  mostly  quite  soluble  in  water,  and 
fairly  so  in  alcohol,  but  dissolve  with  difficulty  in  ether,  chloro- 
form, and  the  oils.  For  example,  atropine,  the  pure  alkaloid, 
is  soluble  in  455  parts  of  water,  in  1.5  parts  of  alcohol  or  chloro- 
form, and  in  25  parts  of  ether;  while  atr  opine  sulphate,  the  salt 
in  common  use,  is  soluble  in  0.38  part  of  water  (less  than  its  own 
weight)  ;  in  5  parts  of  alcohol,  in  420  parts  of  chloroform,  and 
in  3000  parts  of  ether.  Commonly  in  practice  we  employ  the 


22  PHARMACOLOGY   AND   THERAPEUTICS 

salts  only,  but  when  a  solution  is  to  be  made  in  oil,  or  chloroform, 
or  ether,  we  must  use  the  pure  alkaloid. 

Incompatibles. — Alkaloids  have  extensive  chemic  affinities, 
and  there  are  many  reagents  which  are  used  in  the  laboratory  as 
tests  or  precipitants  for  them.  As  physicians,  however,  we  need 
know  only  their  common  prescription  incompatibles,  i.  e.,  those 
substances  which  form  precipitates  with  alkaloidal  salts,  and 
which  we  would  be  likely  thoughtlessly  to  include  in  a  prescrip- 
tion containing  an  alkaloidal  salt.  Such  common  prescription 
incompatibles  are: 

1.  Alkalies,  which  combine  with  the  acid  radicle  and  throw 
the  less  soluble  pure  alkaloid  out  of  solution  (some  of  the  alka- 
loids are  destroyed  by  strong  alkalies). 

2.  Tannic  acid,  which  forms  the  comparatively  insoluble 
tannate. 

3.  Iodine,  iodides,  and  bromides,  which  form  the  compara- 
tively insoluble  iodides  and  bromides,  or  double  salts. 

4.  Mercuric  chloride,  which  forms  insoluble  double  salts. 
In  these  cases  it  must  be  borne  in  mind  that  the  alkaloid  is 

merely  rendered  less  soluble  in  water,  so  if  a  large  volume  of 
water  or  a  fair  percentage  of  alcohol  is  present,  the  precipitation 
may  not  occur. 

Physical  Character. — Most  of  the  alkaloids  are  solids,  as 
morphine,  quinine,  and  strychnine.  A  few  of  them  are  volatile 
liquids,  as  nicotine,  pilocarpine,  coniine,  and  lobeline,  but  these 
latter  mostly  form  non-volatile  solid  salts,  which  can  be  readily 
handled.  Some  are  crystalline,  some  amorphous.  Some  are 
deliquescent  and  liquefy  in  moist  air,  as  pilocarpine  hydro- 
chloride;  others  are  efflorescent  and  lose  weight  in  dry  air,  as  the 
sulphate  of  strychnine  and  the  sulphate  of  quinine.  Some  are 
decomposed  by  the  heat  of  boiling  water;  others  can  stand  much 
higher  temperatures.  Cocaine  is  decomposed  at  about  98°  C. 
(just  below  the  boiling-point  of  water),  and  its  solutions  cannot, 
therefore,  be  sterilized  safely  by  boiling.  Some  which  will 
stand  a  higher  temperature  for  a  short  time  are:  aconitine, 
atropine,  brucine,  cevadine,  codeine,  morphine,  narcotine,  and 
strychnine;  so  that  aqueous  or  alcoholic  liquids  containing  these 
alkaloids  may  be  brought  to  the  boiling-point  without  fear  of 
harm. 

Taste. — The  taste  of  alkaloids  is  bitter — that  of  strychnine 
and  quinine  intensely  so;  that  of  morphine,  codeine,  and  caffeine 
mildly  so. 

Occurrence. — Alkaloids  occur  almost  wholly  in  the  higher 
plants  the  dicotyledons.  A  few  are  found  in  the  lower  plants, 
and  one  of  these,  muscarine,  is  the  poisonous  principle  in  a  few 


THE   CONSTITUENTS   OF   ORGANIC  DRUGS  23 

of  the  poisonous  mushrooms.  Some  plants  furnish  many  alka- 
loids, opium,  for  example,  yielding  about  nineteen,  and  cinchona 
about  thirty-two.  In  some  cases  one  alkaloid  is  found  in  one  part 
of  the  plant  and  another  in  a  wholly  different  part  of  the  same 
plant;  often  several  are  found  together.  Where  a  number  of 
alkaloids  occur  in  one  plant  they  are  usually  closely  related,  both 
chemically  and  pharmacologically,  as  in  the  case  of  the  alkaloids 
of  belladonna;  but  in  some  instances  they  are  quite  different, 
and  may  even  be  pharmacologically  antagonistic,  as  physostig- 
mine  and  calabarine  in  the  Calabar  bean. 

It  is  of  interest  that  some  alkaloids  are  confined  entirely  to 
one  botanical  family,  as  atropine,  which  is  not  found  outside  of 
the  potato  family  (Solanacece) ;  or  to  one  plant  genus,  as  pilo- 
carpine;  or  to  a  particular  species,  as  morphine  in  the  oriental 
poppy,  and  even  then,  perhaps,  only  when  it  is  grown  in  a  par- 
ticular region.  Others,  however,  are  of  wider  distribution,  as 
caffeine,  which  is  found  in  various  parts  of  the  world  in  wholly 
unrelated  plants,  and  berberine,  found  in  the  northeastern  region 
of  the  United  States  in  the  barberry,  hydrastis,  and  moonseed. 

The  amount  of  alkaloid  present  in  different  specimens  of  a 
drug  may  vary  within  wide  limits,  as  might  be  expected  in  plants 
growing  under  such  different  conditions  of  soil,  climate,  and 
weather,  and  subjected  to  different  methods  of  collecting,  drying, 
preserving,  etc.  Yet  the  best  quality  of  most  drugs  is  notably 
uniform  in  its  alkaloidal  content. 

Alkaloids  produced  by  animals  are  more  commonly  known 
as  leukomains  and  ptomains — leukomains,  when  they  are  formed 
by  the  body-cells,  that  is,  are  products  of  metabolism,  for  ex- 
ample, epinephrine;  and  ptomains,  when  they  result  from  micro- 
bic  decomposition  of  dead  material,  especially  the  amino-acids. 
Ptomain-poisoning  from  decomposing  foods  may  closely  resemble 
poisoning  by  plant  alkaloids;  in  fact,  one  ptomain  is  called 
ptomatropine,  because  it  gives  the  symptoms  of  atropine  poison- 
ing. Certain  of  the  alkaloids,  as  choline,  neurine,  xanthine, 
and  some  of  the  ptomains  are  produced  by  both  plants  and  ani- 
mals, so  that  the  dividing- line  is  artificial  and  not  based  on 
chemic  nature. 

Artificial  Alkaloids. — A  number  of  alkaloids  can  be  prepared 
artificially,  and  theophylline,  which  occurs  naturally  in  minute 
quantity  in  tea-leaves,  was  the  first  to  be  produced  synthetically 
on  a  commercial  scale.  Suprarenine,  a  synthetic  with  the  actions 
of  epinephrine,  is  also  marketed.  In  addition,  the  Pharmacopoeia 
recognizes  four  bodies  which  are  manufactured  from  plant 
alkaloids,  viz.,  apomorphine,  prepared  from  morphine  by  dehydra- 
tion; cotarnine,  prepared  by  hydrolizing  narcotine;  homat rapine. 


24  PHARMACOLOGY   AND   THERAPEUTICS 

which  results  from  the  action  of  mandelic  acid  upon  tropine, 
the  mother-substance  of  atropine;  and  hydrastinine,  obtained 
by  the  oxidation  of  hydrastine.  Two  other  artificial  substances 
of  the  Pharmacopoeia,  hexamethylenamine,  or  urotropine,  and 
antipyrine,  have  close  chemic  affiliations  with  the  alkaloid  group. 

That  there  may  be  differences  in  the  physiologic  actions  of 
the  different  salts  of  an  alkaloid  is  suggested  by  the  experiments 
of  O.  H.  Brown,  1907,  on  paramcecium.  For  example,  in  ~ 
solutions  of  quinine  salts  the  paramcecia  lived  in  the  sulphate 
thirty  seconds,  in  the  chloride,  thirty  seconds,  in  the  hypo- 
phosphite,  fifteen  seconds,  in  the  bisulphate,  three  hundred  and 
thirty  seconds.  In  ^  solution  of  strychnine  salts  they  lived 
in  the  acetate  five  seconds,  in  the  nitrate,  forty-five  seconds,  in 
the  sulphate,  seventy  seconds,  in  the  hypophosphite,  seven 
hundred  and  twenty  seconds.  They  were  less  readily  poisoned 
by  ~  solutions  of  morphine  salts,  so  the  percentage  of  para- 
mcecia dead  at  the  end  of  a  given  time  was  taken.  At  the  end 
of  two  hours,  of  those  in  the  acetate  none  were  dead,  while 
of  those  in  the  valerianate  5  per  cent.,  of  those  in  the  sulphate 
60  per  cent.,  and  of  those  in  the  meconate  90  per  cent.,  were 
dead. 

3.  Neutral  Principles. — Besides  acid  and  basic  substances, 
plants  furnish  a  large  number  of  proximate  principles  which  are 
chemically  neutral.  Their  names  end  in  in  (Latin,  inuwi),  in 
accordance  with  the  pharmacopceial  rule  to  distinguish  them 
from  alkaloids,  as  stated  above.  The  most  important  are  the 
glucosides  (glycosides) . 

The  glucosides  are  a  class  of  bodies  which,  under  the  in- 
fluence of  certain  agents,  decompose  and  yield  some  form  of 
sugar,  together  with  one  or  more  other  bodies.  These  decom- 
posing agents  may  be  heat,  dilute  acids,  strong  alkalies,  enzymes, 
bacteria,  or  fungi.  Most  of  the  glucosides  yield  glucose,  whence 
the  name;  a  few  of  them  yield  other  sugars.  Chemically,  they 
are  a  loose  group,  and  beyond  their  readiness  of  decomposition 
and  their  power  to  yield  sugar,  have  no  essential  characters  in 
common.  They  follow  no  rules  as  to  solubility,  or  taste,  or  im- 
portance, some  of  them  being  bitter,  some  not;  some  soluble  in 
water  or  alcohol,  some  not;  some  inert  pharmacologically,  and 
others,  such  as  the  active  principles  of  digitalis,  strophanthus, 
and  cascara,  being  among  our  most  valued  remedies.  The 
only  glucosides  official  in  the  United  States  Pharmacopoeia  are 
salicin,  the  active  principle  of  willow  and  poplar  barks,  and 
strophanthin,  the  active  principle  of  strophanthus.  The  gluco- 
sidal  nature  of  these  bodies  may  be  readily  shown,  for  if  they 
are  warmed  with  dilute  hydrochloric  acid,  the  mixture  will  give 


THE    CONSTITUENTS    OF   ORGANIC   DRUGS  25 

the  glucose  test  with  Fehling's  solution.  The  products  of  the  de- 
composition of  salicin  are  glucose  and  saligenin  (salicyl  alcohol). 

C6Hn05.O.C6H4CH2OH  +  H2O  =  C6H12O6  +  C6H4.OH.CH2OH 
Salicin  Glucose          Salicyl  alcohol 

The  ready  decomposition  of  these  bodies  indicates  that  prep- 
arations of  drugs  such  as  digitalis,  which  depend  upon  glucosides 
for  their  activity,  must  neither  be  mixed  with  strong  alkalies  or 
acids  nor  subjected  to  continued  heat. 

There  are  two  glucosides,  amygdalin  and  sinigrin,  which  are 
practically  inert  pharmacologically,  but  are  of  great  importance 
because  of  the  products  of  their  decomposition  by  certain  en- 
zymes. 

Amygdalin,  with  its  particular  enzyme,  emulsin,  occurs  in 
bitter  almonds,  peach-pits,  wild-cherry  bark,  and  cherry-laurel 
leaves.  In  the  presence  of  water  the  enzyme  emulsin  acts  upon 
the  amygdalin,  causing  it  to  split  up  into  glucose,  hydrocyanic 
acid  (prussic  acid),  and  benzaldehyde.  The  mixture  of  the  two 
latter  constitutes  the  highly  poisonous  volatile  "oil  of  bitter 
almond,"  which  is  required  by  the  Pharmacopoeia  to  contain  not 
less  than  85  per  cent,  of  benzaldehyde  and  not  less  than  2  per 
cent,  nor  more  than  4  per  cent,  of  hydrocyanic  acid. 

Amygdalin  Water        Glucose       Prussic  acid         Benzaldehyde 

C20H27NOu.3H2O  +  2H20  =  2C6Hi2O6    +     HCN       +       C6H6COH     +    3H2O 

The  amygdalin  occurs  in  bitter  almond  to  the  extent  of  1.75 
to  3  per  cent.,  so  that  one  ounce  of  bitter  almonds  would  be  a 
poisonous  dose.  As  enzymes  are  destroyed  by  heat  and  rendered 
inert  by  alcohol,  no  preparation  of  bitter  almond,  wild-cherry 
bark,  or  cherry-laurel  leaves  should  be  made  until  the  drug  has 
first  been  steeped  in  lukewarm  or  cold  water  to  permit  this  enzyme 
action  and  the  development  of  these  products.  If  the  crude  drug 
should  be  extracted  in  the  usual  way  by  alcohol  or  very  hot  water, 
without  preliminary  steeping,  the  preparation  would  be  inert. 
Sweet  almonds  also  contain  emulsin,  but  no  amygdalin,  hence 
are  inert  pharmacologically  and  may  be  swallowed  ad  libitum. 

Sinigrin,  with  its  peculiar  enzyme,  my  rosin,  occurs  in  black 
mustard  seed,  and  to  some  extent  in  horseradish  root.  Mustard 
flour,  as  purchased,  contains  nothing  irritating,  and  has  the  odor 
of  ordinary  flour;  but  as  soon  as  it  is  mixed  with  water,  it  develops 
the  odor  and  irritant  properties  characteristic  of  mustard.  This 
is  because,  in  the  presence  of  water,  the  myrosin  acts  upon  the 
sinigrin  and  splits  it  up  to  yield  glucose,  potassium  bisulphate, 


26  PHARMACOLOGY   AND   THERAPEUTICS 

and  allyl  isothiocyanate,  the  last-named  substance  being  the 
highly  irritating  "volatile  oil  of  mustard." 

Sinigrin  Glucose  Potassium  bisulphate     Allyl  isothiocyanate 

C10HlsNS20,oK  =  C6H1206          +          KHS04          +  C3H6CNS 

As  this  enzyme  is  rendered  inert  by  a  temperature  above 
60°  C.  (140°  F.),  very  hot  water  should  not  be  used  in  preparing 
a  mustard  poultice  or  a  mustard  foot-bath.  It  is  of  interest  that 
this  volatile  oil  of  mustard,  when  shaken  with  alcohol  and  am- 
monia water,  deposits  more  than  its  own  weight  of  crystals  of 
thiosinamine,  a  drug  which  has  been  used  by  injection  for  the 
removal  of  excessive  scar  tissue.  (See  Part  II.) 

C3H5CNS  +  NH3  =  C3H6CSN2H3. 

White  mustard  seed  also  contains  myrosin,  but  instead  of 
sinigrin,  it  contains  another  glucoside,  sinalbin.  Under  the 
influence  of  myrosin  in  the  presence  of  water  sinalbin  splits  up 
into  entirely  different  products,  viz.,  glucose,  sinapine  sulphate 
(an  alkaloidal  salt),  and  acrinyl  isothiocyanate  (an  irritant  but 
non- volatile  oil). 

Phlorhizin  (phloridzin  or  phlorizin)  is  a  glucoside  obtained 
from  the  bark  of  apple,  pear,  cherry,  and  plum  trees,  especially 
the  bark  of  the  root.  It  is  nearly  insoluble  in  cold  water,  but 
readily  soluble  in  alcohol  and  alkaline  liquids.  Its  administra- 
tion is  followed  by  glycosuria  without  hyperglycemia,  the  gly- 
cosuria  resulting  from  changes  in  the  kidneys  by  which  they  are 
made  unable  to  keep  back  the  normal  sugar  in  the  blood;  in 
fact,  there  is  a  hypoglycemia.  In  other  words,  the  "secretion 
threshold"  of  the  kidneys  for  sugar  (Magnus)  is  lowered.  Phlor- 
hizin is  diuretic,  this  action,  according  to  Loewi  (1903),  being 
due  to  the  prevention  of  kidney  reabsorption  by  the  sugar  of 
the  urine.  It  has  been  used  as  a  test  of  the  functional  power  of  the 
kidneys. 

Besides  the  glucosides,  there  are  other  neutral  principles 
of  importance  in  medicine,  such  as  santonin,  aloin,  elaterin, 
chrysarobin,  etc.  Some  of  those  whose  chief  characteristic  is 
bitterness,  as  quassin  of  quassia,  and  chamomillin  of  chamomile, 
are  often  spoken  of  as  bitter  principles  or  amaroids. 

4.  Toxalbumins  or  Toxins. — An  extensive  class  of  poisonous 
compounds,  probably  protein,  of  which  some  occur  in  plants,  some 
constitute  the  poisonous  products  of  bacteria,  and  some  are  the 
poisonous  agents  in  the  venom  of  snakes,  scorpions,  the  tarantula, 
the  Gila  monster,  spiders,  and  other  poisonous  animals. 

It  is  characteristic  of  these  substances  that  their  poisonous 


THE   CONSTITUENTS   OF   ORGANIC   DRUGS  27 

symptoms  come  on  only  after  a  latent  period,  and  that,  in  suscep- 
tible animals,  immunity  to  the  poison  may  be  established  by  the 
repeated  administration  of  small  doses.  This  immunity  is  spe- 
cific, the  immunity  to  one  toxin  conferring  no  protection  from 
poisoning  by  another. 

Aside  from  those  produced  by  bacteria  and  animals,  the  most 
important  known  toxalbumins  are: 

1.  Ricin,  which  occurs  in  the  castor-oil  bean,  the  seed  of 
Ricinus  communis.     The  poisonous  ricin  is  left  behind  in  the 
extraction  of  the  castor  oil;  but  there  have  been  some  cases  of 
poisoning  from  the  ingestion  of  the  whole  seeds.     The  author 
has  met  with  a  case  in  New  York.    The  symptoms  are  violent 
gastro-enteritis  and  collapse. 

2.  Abrin,  which  occurs  in  jequirity  beans  (Abrus  precatorius) , 
the  little  shiny  red  seeds  with  circular  black  spot  which  one  often 
sees  in  the  shops  in  baskets  of  sea-shells.    It  is  used  as  an  irritant 
in  the  eye  in  some  cases  of  corneal  opacity. 

j.  Amanita  toxin,  which  occurs  in  the  death's  head  fungus, 
Amanita  phalloides,  and  is  responsible  for  many  cases  of  mush- 
room-poisoning. (See  under  Muscarine.) 

Hypersusceptibility  to  a  toxalbumin  in  the  pollen  of  certain 
plants  would  seem  to  be  the  explanation  of  the  attacks  of  hay- 
fever  and  hay-asthma  to  which  so  many  people  are  subject 
(Meltzer  and  Auer  and  Wolff-Eisner). 

5.  The  Ferments  or  Enzymes. — The  enzymes  are  a  class  of 
bodies  capable  of  instituting  chemic  changes  without  apparently 
entering  into  the  reaction  or  forming  a  part  of  the  end-products. 
Their  activity  is  very  persistent,  but  not  unlimited.     They  are 
unstable  bodies,  and  are  nearly  all  destroyed  at  a  temperature 
of  about  60°  C.  (140°  F.).    Examples  a,ie:' invertase,  which  trans- 
forms cane-sugar  into  fructose  and  glucose;  lactase,  which  changes 
sugar-of-milk  into  glucose  and  galactose;  maltose,  which  converts 
maltose  into  glucose;  emulsin  and  myrosin,  of  whose  reactions 
with  certain  glucosides  we  have-  spoken,  and  pepsin,  trypsin, 
and  the  other  enzymes  of  the  digestive  tract.     A  number  of 
enzymes  have  a  reversible  action,  i.  e.,  can,  under  certain  circum- 
stances, bring  about  changes  just  the  reverse  of  the  usual. 

It  is  not  improbable  that  a  great  many  of  the  metabolic 
changes  going  on  in  the  animal  body  are  brought  about  by  en- 
zymes. The  oxidases,  for  example,  are  concerned  in  the  oxidation 
processes  of  the  tissues. 

6.  The  Sugars,  Starches,  and  Gums. — These  are  carbohy- 
drates of  very  slight  pharmacologic  action  and  of  little  importance 
as  remedies,  but  of  importance  in  dietetics  and  the  arts. 

Cane-sugar  or  common  sugar  (Latin,  saccJiarum],  CioH^Oii, 


28  PHARMACOLOGY   AND   THERAPEUTICS 

is  employed  to  make  the  various  syrups  and  as  a  sweetening 
agent.  It  is  found  in  abundance  in  the  sap  of  the  sugar  maple, 
in  sugar-cane,  in  sorghum,  and  in  the  root  of  the  sugar-beet.  It 
dissolves  in  half  its  weight  of  water  and  is  insoluble  in  alcohol. 
It  ferments  with  yeast,  but  does  not  reduce  Fehling's  solution. 

Sugar  of  milk  (Latin,  saccharum  lactis),  C^H^On,  is  obtained 
from  milk,  and  requires  for  solution  five  times  its  weight  of  water. 
It  reduces  Fehling's  solution,  but  does  not  ferment  with  yeast. 
It  is  not  very  sweet,  and  is  chiefly  used  as  a  nutritive  in  infant 
feeding  and  typhoid  fever.  In  pharmacy  it  is  employed  as  a 
diluent.  Cheap  brands  of  sugar-of-milk  may  contain  lactic 
acid  and  traces  of  milk  proteins,  which  form  a  nidus  for  bacterial 
growth,  or  they  may  be  adulterated  with  cane-sugar  or  glucose. 

Glwose  (Latin,  glucosum),  C^M^Oe,  is  described  in  Part  II. 

Lemtlose,  C6Hi2O6,  a  form  of  sugar  abundant  in  honey  and 
some  fruits,  is  a  carbohydrate  which  has  been  found  in  many 
instances  to  be  more  easily  appropriated  by  diabetics  than  are 
cane-sugar,  glucose,  and  many  starchy  foods  (von  Noorden). 
It  has  been  used  by  Strauss  as  a  test  of  the  functional  power  of 
the  liver,  the  assertion  being  made  that  if  the  levulose  is  re- 
coverable from  the  urine  unchanged,  the  liver  is  seriously  im- 
paired. In  Foster's  experiments  3  out  of  10  normal  cases  re- 
sponded with  levulosuria,  and  only  14  out  of  20  cases  of  well- 
marked  cirrhosis.  Churchman,  Frey,  and  others  obtained  similar 
results.  The  test  cannot,  therefore,  be  depended  upon. 

Manna,  derived  from  a  tree  of  the  ash  family  (Fraxinus  ornus), 
contains  the  sugar,  mannite,  CeH^O,;,  and  is  laxative. 

Comstar  ch  (amylum),  C6H10O5,  is  the  starch  in  common  use. 
It  is  employed  as  a  dusting-powder  for  the  skin,  or  for  pills  to 
prevent  their  sticking"  together,  or  in  the  form  of  starch  water 
as  a  soothing  injection  in  irritative  conditions  of  the  lower  bowel. 
To  make  starch  water,  the  starch  should  first  be  hydrolyzed  by 
mixing  about  a  teaspoonful  with  two  ounces  of  water,  boiling 
until  it  forms  a  translucent  paste,  then  diluting  with  water  to 
one-half  pint.  It  may  be  made  by  simply  boiling  a  teaspoonful  of 
starch  with  the  requisite  quantity  of  water  at  the  outset,  but 
by  this  method  the  starch  does  not  so  readily  hydrolyze.  Corn- 
starch  and  arrowroot  starch  (maranta)  are  used  as  foods.  The 
latter  has  long  had  the  reputation  of  being  the  best  kind  of  starch 
for  the  feeding  of  children  and  invalids,  but  it  is  not  now  so  much 
employed  as  formerly. 

The  gums  are  chemically  closely  related  to  the  sugars  and 
starches.  There  are  two  official,  viz.,  acacia,  which  consists 
chiefly  of  arabinose,  Ci2H22OnCa,  and  tragacanlh,  which  can  be 
made  to  yield  arabinose. 


THE   CONSTITUENTS   OF   ORGANIC  DRUGS  29 

Acacia  (gum  arable)  is  soluble  in  water  and  is  demulcent. 
Its  chief  uses  are  pharmaceutic,  as  in  the  manufacture  of  muci- 
lage and  emulsions,  and  to  give  increased  viscosity  to  mixtures 
containing  heavy  insoluble  powders  (so  that  the  powder  may  be 
held  in  temporary  suspension  in  the  liquid  during  the  pouring 
of  the  dose).  Its  solutions  ferment  readily,  turn  sour,  and  be- 
come ropy;  and  it  is  precipitated  from  aqueous  solution  by 
alcohol. 

Tragacanth  does  not  dissolve  in  water,  but  swells  up  and 
makes  an  adhesive  paste. 

Dextrin  (C6Hi0O5),  known  as  British  gum,  is  prepared  from 
starch,  being  an  intermediate  stage  in  the  change  of  starch  to 
maltose  or  glucose.  It  is  soluble  in  water,  is  sweetish  to  the  taste 
and  slightly  laxative,  and  is  the  chief  ingredient  of  some  of  the 
proprietary  infant  foods.  It  is  the  gum  generally  used  on  postage- 
stamps,  and  in  paste  form  is  frequently  employed  for  attaching 
labels. 

Cherry-gum  is  an  insoluble  type  of  gum  of  no  medical  interest. 

A  mucilage  is  an  adhesive,  aqueous  liquid  or  paste  made  from 
a  gum.  The  official  mucilages  are  those  of  acacia  and  tragacanth, 
both  used  for  mechanical  purposes. 

7.  The  Tannins  or  Tannic  Acids. — These  are  a  class  of  im- 
perfectly denned  astringent  bodies  of  the  aromatic  group.    They 
are  all  acids  which  form  salts,  and  some  of  them  are  glucosidal 
in  nature.     They  precipitate  alkaloids,  mercuric  chloride,  and 
other  salts  of  the  heavy  metals,  and  also  proteins  and  gelatin. 
With  iron  compounds  they  make  ink  (blue  to  black  in  some  cases, 
green  in  others),  and  with  the  connective  tissue,  protein,  and 
gelatinous  material  of  hides  they  make  leather.     This  suggests 
the  unwisdom  of  administering  a  gelatin-coated  pill  or  capsule 
at  the  same  time  as  a  tannin-containing  drug.     They  are  freely 
but  slowly  soluble  in  water,  and  readily  soluble  in  alcohol  and 
glycerin.     They  occur  mostly  in  the  bark  of  trees,  and  in  the 
plant-galls  which  result  from  punctures  of  insects.    The  various 
tannins  are  given  the  names  of  the  plants  which  yield  them,  e.  g., 
that  from  cinchona  is  called  cinchotannin,  or  cinchotannic  acid, 
that  from  kino  is  kinotannic  acid,  etc.    The  official  "tannic  acid" 
is  quercitannin,  and  is  derived  from  oak-galls.     It  is  considered 
in  Part  II. 

8.  The  Fixed  Oils,  Fats,  and  Waxes. — (a)  The  fixed  oils  and 
fats  are  mixtures  of  the  three  bodies,  olein  (liquid),  palmitin 
(semisolid),  and  stearin  (solid),  or  close  relatives  of  these,  and 
in  addition  usually  small  amounts  of  other  bodies.     Olein,  pal- 
mitin,  and    stearin    are   compounds   of  glyceryl,   C3H5=,   with 
radicles  of  the  various  fatty  acids.     With  alkalies  they  form 


30  PHARMACOLOGY  AND  THERAPEUTICS 

soaps  and  glycerin.     Castile  soap,  for  example,  is  made  by  the 
action  of  sodium  hydroxide  on  olive  oil,  which  is  nearly  pure  olein: 


2)3  +  3NaOH    =  3NaC18H33O2  +  C,HS(OH), 
Olein  Sodium         Castile  soap          Glycerin 

hydroxide 

The  oils  differ  from  the  fats  only  in  the  relative  proportions 
of  these  basal  ingredients,  the  oils  having  more  of  the  olein,  which 
gives  them  a  liquid  consistence  at  ordinary  temperatures,  and  the 
fats  more  of  the  stearin  and  palmitin,  which  make  them  solid  or 
semisolid. 

The  fats  and  fixed  oils  have  a  greasy  feeling  and  are  non- 
volatile, so  that  they  leave  a  permanent  grease-spot.  They  can- 
not be  distilled,  for  by  heat  they  are  decomposed,  with  the  genera- 
tion of  disagreeable  acrid  vapors  (the  familiar  odor  of  burning 
grease).  They  are  insoluble  in  water  and  alcohol  (except  castor 
oil  and  croton  oil,  which  dissolve  in  alcohol),  and  are  readily 
soluble  in  ether,  chloroform,  and  benzin.  They  are  almost  all 
bland,  non-irritating  substances  with  nutrient  and  emollient 
properties;  but  on  exposure  to  the  air  they  gradually  become 
rancid  by  the  liberation  of  odorous  and  irritating  fatty  acids. 
Linseed  oil  (oleum  lini),  if  exposed  to  the  air  in  thin  layers,  will 
dry  like  varnish,  but  most  of  the  oils  are  of  the  non-drying  type. 
A  few  of  the  fats  and  oils  are  of  animal  origin,  e.  g.,  butter,  lard 
(adeps),  tallow,  suet  (sevum),  and  cod-liver  oil  (oleum  morrhuae)  ; 
but  the  majority  are  of  vegetable  origin,  as  almond,  cotton- 
seed, cocoanut,  linseed,  olive  and  peanut  oils,  and  cocoa-butter. 
These  are  found  chiefly  in  seeds  or  in  fruits,  the  best  qualities 
being  usually  obtained  with  the  least  compression  necessary  and 
in  the  cold;  the  poorer  qualities  by  expression  between  heated 
plates.  They  may  also  be  extracted  by  a  suitable  solvent,  such 
as  benzin,  which  is  afterward  removed  by  distillation. 

Cocoa-butter  or  cacao-butter  (oleum  theobromatis)  is  obtained 
from  chocolate-seeds  by  compression  between  hot  or  cold  plates. 
The  fat  is  the  cocoa-butter,  and  the  residue  constitutes  "cocoa." 
This  fat  has  a  very  slight  odor  and  taste  of  chocolate,  is  firm  and 
rather  brittle  at  ordinary  temperatures,  melts  at  the  temperature 
of  the  body,  and  does  not  readily  become  rancid.  It  is  used  as  a 
basis  for  the  manufacture  of  suppositories,  these  retaining  their 
shape  at  ordinary  temperatures  and  quickly  melting  when  in- 
serted into  a  body  orifice,  such  as  the  rectum. 

Castor  oil  (oleum  ricini)  and  croton  oil  (oleum  tiglii)  differ 
from  the  other  fixed  oils  in  being  soluble  in  alcohol  and  in  possess- 
ing special  cathartic  properties.  (See  Part  II.)  Castor  oil  is 
sometimes  added  to  alcoholic  hair  lotions  to  prevent  drying  of 
the  scalp  (about  10  minims  to  a  3-ounce  bottle). 


THE    CONSTITUENTS    OF   ORGANIC   DRUGS  3! 

Glycerin  (glycerinum)  is  a  product  of  the  saponification  of 
fats  or  fixed  oils.  (See  Reaction,  page  29.)  It  is  thick  and  viscid, 
has  a  sweet  taste,  mixes  freely  with  water  and  alcohol,  and  has 
great  affinity  for  water.  It  has  extensive  employment  in  phar- 
macy as  a  solvent,  as  a  softening  agent  and  preservative,  and  as 
a  means  for  increasing  the  viscosity  of  liquids. 

Action  and  Uses. — Applied  in  concentrated  form  to  mucous 
membranes,  it  is  astringent,  causing  the  superficial  cells  to  shrink 
by  abstraction  of  water.  For  this  reason  it  is  used  as  an  applica- 
tion to  a  relaxed  uvula  or  pharynx.  Diluted  with  water  or  rose- 
water,  as  in  "rose-water  and  glycerin"  (two  parts  to  one)  and  in 
"calamine  lotion"  (see  Zinc  Carbonate),  it  is  used  upon  the  skin 
as  an  emollient,  serving  to  prevent  the  drying  of  the  epithelium. 
With  lemon-juice  or  rose-water  it  is  also  used  as  an  application  to 
the  dry  tongue  of  fever  patients.  In  mixtures  for  internal  use  it 
serves  as  a  sweetening  agent  and  is  slightly  laxative.  In  diabetes 
it  tends  to  increase  the  glycosuria.  For  use  in  the  rectum  as  a 
mild  irritant  and  lubricant  it  may  be  added  to  an  ordinary  enema, 
or  used  in  the  form  of  glycerin  suppositories  (suppositoria  glyc- 
erini),  which  hold  95  per  cent,  of  glycerin.  To  soften  hard  feces, 
|  ounce  (15  c.c.)  may  be  added  to  half  a  pint  of  soapsuds.  Hertz, 
in  "The  Sensibility  of  the  Alimentary  Canal,"  1911,  states  that 
glycerin  acts  as  an  irritant  to  the  anal  canal,  but  not  to  the  rectum. 
The  glycerites  are  a  class  of  official  preparations  in  which  glycerin 
is  the  solvent. 

Soaps. — The  soluble  or  detergent  soaps  are  prepared  by  the 
action  of  an  alkali  upon  a  fat  or  oil,  the  potash  soaps  being  soft, 
and  those  of  soda  being  hard.  They  contain  glycerin  unless 
this  is  removed  by  washing,  are  soluble  in  alcohol  and  water, 
and  have  an  alkaline  reaction. 

Soap  (sapo),  Castile  or  hard  soap,  is  prepared  by  the  action 
of  sodium  hydroxide  on  olive  oil.  It  is  used  in  the  manufacture 
of  pills,  soap  liniment,  chloroform  liniment,  and  saponified  tooth 
powders.  (For  the  chemic  reaction  see  above,  under  "Fixed 
Oils  and  Fats.")  Some  time  ago  a  proprietary  house  put  out  a 
preparation  described  as  acid  sodium  oleate.  It  was  extensively 
prescribed  by  physicians,  though  it  was  nothing  but  Castile  soap 
containing  free  fatty  acid. 

Soft  soap  or  green  soap  (sapo  mollis)  is  prepared  from  potas- 
sium hydroxide  and  linseed  oil,  without  the  removal  of  the  de- 
veloped glycerin,  and  is  employed  extensively  for  cleansing  the 
hands  and  skin  preparatory  to  operative  work.  A  liquefied  form 
of  it  is  the  liniment  of  soft  soap  (linimentum  saponis  mollis), 
commonly  called  the  "tincture  of  green  soap,"  made  by  dissolving 
soft  soap  in  alcohol  and  adding  oil  of  lavender  flowers. 


32  PHARMACOLOGY  AND  THERAPEUTICS 

Lipoids  or  Fat  Allies. — Those  of  interest  to  us  are  lecithin  and 
cholesterol.  Lecithin  is  found  in  certain  animal  tissues,  especially 
the  central  nervous  system  and  the  yolk  of  egg.  Of  the  fatty 
substances  of  the  latter,  it  constitutes  about  70  per  cent.  It  is  a 
compound  of  glycerin  and  choline  with  stearic,  palmitic,  and 
phosphoric  acids,  and  is  chemically  a  complex  glycerophosphate. 
It  can  be  saponified  by  alkalies.  (See  Phosphorus.) 

Cholesterol,  a  monatomic  alcohol,  C26H43OH,  is  a  crystalline 
body  found  in  all  forms  of  protoplasm,  but  especially  in  brain 
tissue.  It  also  occurs  in  abundance  in  the  yolk  of  egg,  in  milk, 
cream,  and  butter,  and  in  the  bile.  Gall-stones  are  frequently 
the  result  of  its  precipitation  in  the  bile-ducts  or  gall-bladder. 
It  has  been  suggested  in  anemia,  especially  pernicious  anemia, 
in  doses  of  15  grains  (i  gm.)  three  times  a  day;  but  it  is  best 
given  in  the  form  of  milk  and  eggs.  Quite  probably  it  plays  no 
role  in  therapeutics. 

Lanolin  (adeps  lanae  hydrosus),  the  purified  fat  of  the  wool 
of  sheep,  mixed  with  30  per  cent,  of  water,  is  made  up  of  com- 
pounds of  various  fatty  acids  with  isocholesterin.  It  is  thus  not 
a  glyceryl  fat,  but  a  cholesterin  fat,  and  is  often  classed  with  the 
waxes.  It  is  yellowish  white,  of  soft,  sticky  consistence,  and, 
unlike  the  glyceryl  fats,  cannot  be  saponified  by  boiling  with  an 
aqueous  solution  of  potash.  Its  greatest  interest  for  us  consists 
in  its  power  to  absorb  more  than  its  own  weight  of  water,  which 
makes  it  of  use  as  an  ointment  base  for  substances  in  aqueous 
solution.  It  is  a  secretion  of  the  sebaceous  type,  not  absorbable 
by  the  sheep's  skin.  As  to  its  absorbability  by  the  human  skin 
there  are  conflicting  reports,  but  most  observers  claim  ready 
absorption.  Patschkowski  applied  an  ointment  of  lanolin  and 
potassium  iodide  and  obtained  iodine  in  the  urine  in  half  an 
hour.  Bloor  states  that  it  is  not  absorbed  when  administered 
by  mouth. 

The  waxes  are  esters  of  the  fatty  acids  with  hydrocarbon 
radicles  higher  in  the  series  than  glyceryl.  They  are  of  firmer 
consistence  than  the  fats,  have  a  higher  melting-point,  and  cannot 
be  saponified  by  boiling  with  an  aqueous  solution  of  potash. 

Beeswax  is  from  the  honey-bee,  and  is  known  in  pharmacy  as 
yellow  wax  fcera  flava).  When  bleached  it  is  called  white  wax 
(cera  alba).  It  is  chiefly  myricyl  palmitatc,  C3oH6i.CifiH3iO2. 

Spermaceti  (cetaceum)  is  obtained  from  the  head  of  the 
sperm-whale,  a  single  whale  yielding  many  barrels.  It  consists 
chiefly  of  cetyl  pulinitute,  CwHw-CieHsiOs.  The  best  "cold- 
creams"  contain  spermaceti  and  white  wax;  the  poor  ones  are 
made  of  tallow. 

The  ointments  or  salves  in  common  use  are  prepared  mostly 


THE   CONSTITUENTS   OF   ORGANIC  DRUGS  33 

from  lard,  suet,  lanolin,  white  wax,  yellow  wax,  spermaceti,  and 
petrolatum  (a  mineral  product). 

The  mineral  oils  do  not  belong  among  the  constituents  of 
organic  drugs,  but  for  convenience  may  be  mentioned  with  the 
other  oils.  They  are  petroleum  products,  are  mixtures  of  hydro- 
carbons, and  are  not  subject  to  rancidity.  The  official  petroleum 
products  are: 

Petroleum  benzin  (benzinum  purificatum — see  Part  II). 
(Kerosene  oil  is  a  limpid  petroleum  product  from  which,  for 
safety,  the  more  volatile  hydrocarbons  are  removed  by  distilla- 
tion. It  is  not  official.) 

Liquid  petrolatum  (liquid  paraffin)  is  a  much  heavier  and  more 
oily  liquid  than  kerosene.  Trade  names  for  some  of  its  slight 
modifications  are  "liquid  albolene"  and  "liquid  vaseline."  It 
has  a  specific  gravity  of  0.828  to  0.905  at  25°  C.  That  having  a 
viscosity  of  3.1  or  over  is  known  as  "heavy  liquid  petrolatum/' 
and  that  with  a  viscosity  of  3  or  less  is  "light  liquid  petrolatum." 

Petrolatum  (petrolatum)  is  practically  what  we  know  as  vase- 
line. The  Pharmacopoeia  specifies  "without  odor  or  taste." 

White  petrolatum  (petrolatum  album),  a  decolorized  product, 
has  been  marketed  under  the  trade  names  of  "solid  albolene" 
and  "white  vaseline." 

Par  a  fin  (paraffinum)  is  a  white,  waxy  solid,  the  purified 
residue  left  after  the  liquid  portion  of  the  crude  petroleum  has 
been  removed. 

Petrolatum  and  white  petrolatum  are  of  ointment  consist- 
ence, and  have  the  advantage  in  ointments  of  not  becoming 
rancid.  But  their  value  in  ointments  is  limited,  as  they  are  not 
absorbed  through  the  skin  and  do  not  readily  penetrate  animal 
and  vegetable  parasites.  In  intestinal  or  pancreatic  fistulas, 
vaseline  and  paraffin,  being  non-saponifiable,  have  been  found 
efficient  in  protecting  the  skin  from  erosion;  while  the  salves  con- 
taining lard  or  other  animal  or  vegetable  fats  become  saponified 
by  the  alkaline  secretions  and  are  useless  or  harmful.  Rovsing 
recommends  vaseline  as  an  injection  into  the  joint  in  dry  arthri- 
tis; and  Wilkie,  the  liquid  vaseline  to  prevent  adhesions  in  ab- 
dominal surgery.  The  writer  has  employed  liquid  petrolatum 
in  the  dry  joints  of  rheumatoid  arthritis  with  temporary  benefit. 
Liquid  petrolatum  is  used  as  the  vehicle  in  oily  sprays  for  nose 
and  throat,  as  the  agent  of  suspension  of  the  insoluble  salts  of 
mercury  for  hypodermatic  use,  as  a  softening  enema  for  hard 
feces,  and  by  mouth,  as  a  mild  laxative;  dose,  i  ounce  (30  c.c.) 
two  or  three  times  a  clay.  (See  Cathartics,  Part  II.)  Kerosene 
and  liquid  petrolatum,  taken  internally,  are  completely  unab- 
sorbed,  and  serve  merely  to  increase  the  bulk  of  the  intestinal 
3 


34  PHARMACOLOGY   AND   THERAPEUTICS 

contents  and  to  soften  the  feces.  They  retard  the  emptying  of 
the  stomach.  Paraffin  with  added  resorcin,  eucalyptol,  or  other 
antiseptics  is  used  to  make  a  wax  dressing  for  burns. 

9.  The  Volatile  Oils. — These  are  the  substances  to  which 
many  plants  owe  their  characteristic  or  essential  odors.  On  this 
account  they  are  often  spoken  of  as  "essential  oils,"  or  as  the  "es- 
sences" of  plants. 

They  differ  from  the  fixed  oils  in  that— 

1.  They  are  volatile,  therefore  can  be  distilled  and  do  not 
leave  a  permanent  grease  stain. 

2.  They  do  not  form  soaps  with  alkalies. 

3.  They  are  soluble  enough  in  water  to  impart  to  it  their  odor 
and  taste. 

4.  They  do  not  become  rancid,  but  on  exposure  to  light  and 
air  tend  to  oxidize  and  resinify. 

They  mix  freely  in  any  proportions  with  chloroform,  ether, 
and  the  fixed  oils,  and  are  all  soluble  in  absolute  alcohol.  Some, 
like  oil  of  turpentine,  require  several  times  their  own  weight  of 
official  alcohol  for  complete  solution.  They  are  all  mixtures, 
some  of  them  quite  complex. 

Occurrence. — Most  of  them  are  found  in  plants,  and  each  in 
a  definite  part  of  the  plant  from  which  it  is  derived,  e.  g.,  oil  of 
orange  in  the  rind  of  the  fruit;  oil  of  cinnamon  in  the  bark;  oil  of 
rose  in  the  petals.  From  these  parts  they  are  obtained  either  by 
distillation  or  by  means  of  a  suitable  solvent,  such  as  benzin, 
which  is  afterward  removed.  Some  of  the  delicate  essential  oil? 
used  in  perfumery,  as  violet  and  heliotrope,  are  obtained  by 
spreading  the  petals  or  flowers  between  wax  plates,  and  after 
ward  separating  the  absorbed  oil  from  the  wax. 

A  few  of  the  volatile  oils  do  not  exist  in  the  living  plant,  ancf 
are  formed  either  by  the  action  of  ferments  on  glucosides  in  the 
presence  of  water,  as  the  oil  of  bitter  almonds,  or  by  destructive 
distillation.  These  latter  are  known  as  empyrciimalic  oils. 

For  convenience,  the  volatile  oils  preexisting  in  the  plant  may 
be  grouped  according  to  their  nature,  and  those  developed  in  the 
plant  part  by  artificial  means  may  be  grouped  according  to  their 
method  of  production. 

11.  Terpenes,    CXHX    (oils    of    turpentine,    juniper, 
2.  Terpenes  +  stearoptens  (oils  of  lemon,  pepper- 
mint,  etc.). 

B.  Xot  existing  in   plant   as  f  ^.  From  enzyme  action  foils  of  mustard  and  bitter 
such,     but     developed  •(  almond), 

from  plant  constituents:  (  4.  Empyreumatic  (oil  of  cade,  oil  of  tar,  creosote). 

Group  i  is  composed  of  oils  which  are  mixtures  of  terpenes 


THE    CONSTITUENTS   OF   ORGANIC  DRUGS  35 

(hemiterpenes,  terpenes,  sesquiterpenes,  diterpenes,  pinene,  etc., 
CioHie),  the  simplest  hydrocarbon  oils  of  the  aromatic  series.  Of 
all  the  volatile  oils,  they  are  the  least  soluble  in  water  and  the 
most  ready  to  resinify  and  deteriorate.  Examples  are:  the  oils 
of  copaiba,  cubebs,  erigeron,  juniper,  and  turpentine.  The  last 
named  consists  almost  wholly  of  dextrorotary  pinene. 

Group  2  includes  the  mixtures  of  terpenes  which  are  holding 
in  solution  one  or  more  oxygenated  bodies  (of  variable  chemic 
nature,  as  aldehydes,  ketones,  ethers,  acids,  etc.).  The  terpene 
portion  is  known  as  the  eleopten,  and  the  oxygenated  portion  as 
the  stearopten.  The  latter  is  usually  solid,  though  sometimes 
liquid.  It  can  be  separated  from  the  eleopten  by  cold  (as  the 
menthol  of  peppermint  oil)  or  by  fractional  distillation.  It  is 
not  always  readily  soluble  in  95  per  cent,  alcohol.  Examples  of 
stearoptens  which  are  separated  and  used  by  themselves  are 
camphor  and  menthol.  It  is  to  the  stearopten  that  the  charac- 
teristic odor  of  these  oils  is  chiefly  due,  but  the  amount  of  stearop- 
ten present  varies  with  the  different  oils.  For  example,  the  oils 
of  orange  or  lemon  contain  only  a  small  percentage  of  their  pecu- 
liar stearopten  and  are  nearly  all  eleopten,  while  the  oils  of  winter- 
green  and  birch  are  almost  entirely  composed  of  a  liquid  stea- 
ropten, which  chemically  is  methyl  salicylate. 

The  oils  of  this  group  are  for  the  most  part  more  soluble  in 
water,  and,  because  of  the  stearopten,  more  agreeable  in  flavor 
than  those  of  Group  i ,  so  they  are  largely  used  in  the  manufacture 
of  the  medicated  waters  and  spirits.  Some  of  them  are  heavier 
than  water,  as  the  oil  of  cinnamon. 

Group  3  contains  those  oils  which  do  not  preexist  in  the  living 
plant,  but  result  from  ferment  action  in  the  presence  of  water. 
The  official  ones  are  the  oil  of  bitter  almond  and  the  volatile  oil 
of  mustard.  (For  the  reactions  in  the  development  of  these  oils 
see  under  Glucosides  above.) 

Group  4  contains  the  empyreumatic  oils,  those  which  do  not 
preexist  in  the  plant,  but  result  from  its  destructive  distillation. 
The  official  ones  are :  Oil  of  cade  (oleum  cadinum) ,  from  juniper 
wood,  and  oil  of  tar  (oleum  picis  liquidae),  from  the  wood  of  Pinus 
palustris  and  other  species  of  pine.  Both  have  a  tarry  odor, 
and  are  added  to  ointments  for  the  treatment  of  chronic  skin 
diseases.  The  syrup  of  tar  (syrupus  picis  liquidae),  in  dose  of  15 
minims  (i  c.c.),  is  also  used  as  an  expectorant. 

Creosote  is  a  mixture  of  phenols  and  phenol  derivatives,  ob- 
tained during  the  distillation  of  wood-tar,  and  has  some  of  the 
properties  of  a  volatile  oil.  The  beechwood  creosote  is  considered 
best  for  medicinal  purposes. 

The  volatile  oils  have  marked  pharmacologic  actions,  but  do 


36  PHARMACOLOGY   AND   THERAPEUTICS 

not  belong  to  a  single  pharmacologic  group.     Their  action  will 
be  considered  in  Part  II. 

10.  The  resins  are  all,  or  nearly  all,  mixtures  of  several  differ- 
ent substances.     They  are  an  ill-defined  group,  forming  amor- 
phous masses  which  have  a  conchoidal  shining  fracture.    They 
are  insoluble  in  water  and  soluble  in  ether,  chloroform,  and  the 
volatile  oils.    Many,  but  not  all,  of  them  are  soluble  in  alcohol, 
and  most  of  them  dissolve  in  alkali  with  the  formation  of  a  non- 
detergent  resin-soap,  which  is  miscible  with  water.    Their  com- 
position is  still  a  subject  of  study.    Some  of  them,  and  perhaps  all 
of  them,  are  formed  by  the  oxidation  of  volatile  oils,  in  association 
with  which  in  the  plant  they  mostly  occur.    Common  rosin,  and 
the  resins   of  jalap,  podophyllum,  and  scammony  are  official 
resins. 

11.  The  oleoresins  are  the  natural  plant  exudates  which  con- 
tain both  volatile  oil  and  resin.    Balsam  of  copaiba,  Canada  bal- 
sam, and  crude  turpentine  are  examples,  common  rosin  and  oil 
of  turpentine  being  the  components  of  crude  turpentine.    (These 
natural  oleoresins  must  be  distinguished  from  the  pharmaceutic 
oleoresins,  which  are  artificial  ethereal  extracts  of  oily  and  resin- 
ous drugs,  i.  e.,  extracts  made  with  ether.) 

12.  The  gum  resins  are  generally  oleoresins  in  natural  ad- 
mixture with  gum.    They  are  obtained  by  the  evaporation  of  the 
milky  juices  of  certain  plants.     On  rubbing  a  gum  resin  with 
water  the  gum  dissolves,  and  with  the  oil  and  resin  forms  a  milky 
emulsion.    Asafetida  and  gamboge  are  examples. 

13.  The  balsams  are  resinous  or  oleoresinous  exudates  which 
contain  benzoic  or  cinnamic  acid,  or  both.    These  latter  impart 
a  "balsamic"  odor.    Benzoin,  storax,  balsam  of  Tolu,  and  balsam 
of  Peru  are  official  examples.     Many  fragrant  substances  are 
incorrectly  called  "balsam,"  e.  g.,  balsam  of  copaiba  and  Canada 
balsam,  both  of  which  are  oleoresins.    In  some  instances  the  resins, 
oleoresins,  gum  resins,  and  balsams  are  the  only  commercial 
representatives  of  their  respective  plants. 

Keratin  is  obtained  from  horn  by  dissolving  out  the  albumin- 
ous matter  with  artificial  digestion,  and  macerating  the  residue 
in  ammonia.  It  is  soluble  in  alkalies  and  insoluble  in  acids,  and 
is  employed  as  a  coating  for  pills  and  capsules  which  it  is  desired 
to  have  pass  through  the  stomach  without  action — the  so-called 
"enteric"  pills.  Theoretically,  if  the  pills  are  given  after  meals, 
the  coating  should  not  dissolve  in  the  stomach,  and  the  medicinal 
agents  should  be  set  free  only  when  the  pills  reach  the  alkaline 
intestinal  contents.  As  a  matter  of  fact,  however,  commercial 
keratin  is  not  always  proof  against  disintegration  in  the  stomach, 
and  as  a  coat  in"  must  be  considered  unreliable. 


PHARMACEUTIC   PREPARATIONS  37 

PHARMACEUTIC  PREPARATIONS 

The  chemicals  and  the  various  mineral,  plant,  or  animal 
crude  drugs  may  be  employed  in  medicine  as  such  without  change, 
e.  g.,  sodium  bicarbonate  or  cod-liver  oil,  or  powdered  digitalis 
leaves;  or  they  may  be  made  into  pharmaceutic  preparations,  as 
the  rhubarb  and  soda  mixture,  the  emulsion  of  cod-liver  oil,  or  the 
tincture  of  digitalis. 

Pharmaceutic  preparations  are  the  prepared  forms  into  which 
drugs  are  made  for  convenient  employment  in  medicine.  It  is 
not  convenient,  for  instance,  to  administer  cinchona  in  the  form 
of  cinchona  bark.  It  would  be  a  disagreeable  task  for  a  patient 
to  chew  the  bitter  bark,  and  difficult,  because  of  the  inert  matter 
present,  to  obtain  in  this  way  the  full  physiologic  activity  of  the 
drug.  But  the  tincture  of  cinchona,  a  pharmaceutic  preparation, 
represents  the  full  physiologic  activity  of  the  drug,  because  the 
active  principles  are  held  in  solution,  and  it  is  easily  administered. 

In  the  preparation  the  drug  or  drugs — (a)  may  remain  un- 
changed, as  in  the  emulsion  of  cod-liver  oil,  rhubarb  pills,  or 
powder  of  ipecac  and  opium  (Dover's  powder);  or  (b)  may  be 
changed  by  chemic  reaction,  as  in  Fowler's  solution  or  Basham's 
mixture;  or  (c)  may  be  made  to  yield  their  active  constituents 
to  a  suitable  solvent,  as  in  preparations  made  by  extraction. 
Preparations,  too,  may  be  employed  in  the  manufacture  of  other 
preparations,  as  cinnamon  water  in  making  chalk  mixture,  and 
the  extract  of  belladonna  in  making  a  belladonna  plaster. 

Extraction  is  the  process  of  obtaining  the  active  constituents 
of  an  animal  or  vegetable  drug  by  means  of  a  suitable  solvent. 
By  this  process  the  inert  woody  fiber,  cellulose,  and  other  matters 
that  are  insoluble  in  the  solvent  employed  are  left  behind,  so 
that  only  the  soluble  matters  of  the  crude  drug  appear  in  the 
preparation.  In  extraction  the  solvent  is  known  as  the  men- 
struum, and  this  differs  with  the  different  drugs  or  types  of  prep- 
aration. It  may  be  water,  alcohol,  alcohol  and  water,  alcohol 
and  glycerin,  glycerin,  wine,  acetic  acid,  ether,  chloroform,  etc. 
Official  preparations  made  by  extraction  are: 

A.  With  aqueous  solvent — infusions  and  decoctions. 

B.  With  alcoholic  solvent  (in  most  instances) — extracts,  fluid- 

extracts,  and  tinctures. 

C.  With  wine — wines. 

D.  With  diluted  acetic  acid — vinegars. 

E.  \Vith  ether — oleoresins. 

Preparations  made  by  extraction  represent  the  activity  of  the 
crude  drug,  but  in  addition  to  the  active  principles,  always  con- 
tain more  or  less  physiologically  inert  matter  which  has  gone  into 


38  PHARMACOLOGY   AND   THERAPEUTICS 

the  solution.  Such  inert  matter  is  known  as  the  "extractive," 
and  it  consists  of  such  substances  as  fat,  wax,  oil,  tannin,  chloro- 
phyll, etc.  Such  "extractive"  is  mostly  colloidal  in  nature,  and 
has  a  tendency  to  retard  the  absorption  and  the  activity  of  the 
active  constituents. 

Percentage  Strength  of  Liquids. — There  are  two  types  of 
percentage  liquids — the  chemic  and  the  pharmaceutic.  The 
chemic  percentage  liquid  deals  only  with  weight,  as  chemic  reac- 
tions involve  relative  weights  regardless  of  volume.  To  make  a 
20  per  cent,  chemic  solution,  20  grams  of  the  substance  to  be 
dissolved  are  mixed  with  So  grams  of  solvent;  therefore,  100 
grams  (weighed)  of  the  solution  would  furnish  20  grams  of  the 
contained  ingredient.  In  the  pharmaceutic  percentage  liquid, 
however,  solids  are  weighed  and  liquids  measured,  so  that  in 
making  a  20  per  cent,  pharmaceutic  solution  20  grams  of  the 
substance  to  be  dissolved  are  mixed  with  enough  solvent  to  make 
the  total  measure  100  c.c.  Of  such  solution,  100  c.c.  (measured) 
will  contain  20  grams  of  the  drug.  In  the  practice  of  medicine, 
liquid  remedies  are  always  administered  by  measure,  for  one  can- 
not carry  scales  to  the  bedside;  therefore  the  United  States 
Pharmacopoeia  adopts  the  pharmaceutic  percentage  liquid,  so 
that  a  given  measure  will  contain  an  easily  calculated  amount  of 
each  essential  ingredient.  The  volumetric  solutions  used  in  chemic 
analysis  are  made  on  the  same  plan.  By  this  method  a  very  sol- 
uble chemical,  such  as  potassium  iodide,  may  be  had  in  100  per 
cent,  solution. 

As  an  illustrative  example  of  the  difference  between  the  chemic 
and  the  pharmaceutic  percentage  liquid,  let  us  take  a  10  per  cent, 
solution  of  cocaine  hydrochloride  in  normal  saline.  In  the  phar- 
maceutic solution,  10  grams  of  the  cocaine  salt  are  dissolved  in  a 
quantity  of  normal  saline,  and  sufficient  normal  saline  added  to 
make  the  finished  solution  measure  100  c.c.  Of  this  solution,  a 
measure  of  10  c.c.  will  give  i  gram  of  the  cocaine  salt,  a  measure 
of  i  c.c.  will  give  o.i  gram,  and  there  is  a  simple  relation  between 
the  measure  of  the  solution  and  the  amount  of  cocaine  it  contains. 
In  the  chemic  solution  10  grams  of  the  cocaine  salt  are  dissolved 
in  90  grams  of  the  normal  saline,  so  that  if  one  wished  to  use  o.i 
gram  of  cocaine  hydrochloride,  one  could  not  get  it  by  measure, 
since  there  is  no  easily  calculated  relation  between  the  measure 
ol  the  liquid  and  the  weight  of  its  dissolved  constituents;  there- 
fore, one  would  have  to  weigh  off  i  gram  of  the  solution.  Such 
weighing  cannot  be  done  in  practice,  therefore  the  chemic  percent- 
age method  is  not  suitable  for  liquids  for  medicinal  use. 

To  conform  with  the  idea  of  weighing  solids  and  measuring 
liquids  the  Pharmacopoeia  specifies  that  in  liquid  preparations 


PHARMACEUTIC   PREPARATIONS  39 

made  by  extraction  a  definite  weight  of  the  drug  shall  be  employed 
in  making  a  definite  volume  of  the  finished  preparation.  Hence 
these  preparations  have  a  definite  relation  in  strength  to  the  drug 
from  which  they  are  made,  for  the  active  ingredients  of  a  definite 
weight  of  the  drug  are  in  the  solution.  The  strengths  of  pharma- 
ceutic  preparations  are  indicated  by  the  amount  of  drug  used  in 
their  making,  whether  the  drugs  themselves  are  in  the  finished 
preparation  or  only  their  extracted  constituents.  Thus  a  measure 
of  TOO  c.c.  of  the  tincture  of  digitalis  represents  the  medicinal 
activity  of  10  grams  of  digitalis  leaves;  the  tincture  is,  therefore, 
of  10  per  cent,  strength.  A  measure  of  100  c.c.  of  the  fluid- 
extract  of  cascara  represents  the  medicinal  activity  of  100  grams 
of  cascara,  hence  the  fluidextract  is  of  100  per  cent,  strength. 

Pharmaceutic  preparations  are  simple  or  compound.  The 
simple  preparations  represent  the  activity  of  one  drug  only;  the 
compound  preparations,  the  activity  of  more  than  one  drug. 
For  example,  rhubarb  pills  have  rhubarb  as  the  only  constituent, 
while  compound  rhubarb  pills  contain  rhubarb,  aloes,  myrrh, 
and  oil  of  peppermint. 

Nomenclature. — The  simple  preparations  are  given  simply 
the  name  of  the  drug  prefixed  by  the  name  of  the  kind  of  prepara- 
tion, as:  Syrup  of  ginger  (syrupus  zingiberis),  infusion  of  digitalis 
(inf usum  digitalis) .  The  compound  preparations  have  two  types 
of  nomenclature.  If  the  active  drugs  are  only  two  in  number, 
or  in  some  cases  three,  all  are  mentioned  in  the  name,  as:  Pills 
of  aloes  and  iron  (pilula  aloes  et  ferri),  elixir  of  the  phosphates 
of  iron,  quinine,  and  strychnine  (elixir  ferri,  quininae  et  strych- 
nine phosphatum) .  If  the  important  drugs  are  several  in  number, 
especially  if  one  overshadows  the  others  in  importance,  only  one 
drug  is  named,  and  the  name  of  the  class  of  preparation  is  modified 
by  the  term  compound.  Examples  are:  Compound  tincture  of 
cinchona  (tinctura  cinchona?  composita),  which  is  made  of  cin- 
chona, serpentaria,  and  bitter-orange  peel;  compound  licorice 
powder  (pulvis  glycyrrhizas  compositus),  which  contains  glycyr- 
rhiza,  senna,  and  sulphur;  and  compound  rhubarb  pills,  men- 
tioned above. 

A  few  compound  preparations  of  this  kind  do  not  bear  a  drug 
name,  but  the  name  which  indicates  their  use  in  medicine,  as 
compound  cathartic  pills  (pilulae  catharticae  compositae). 

DEFINITIONS  OF  THE  KINDS  OF  PHARMACEUTIC  PREPARATIONS 

IN  COMMON  USE 

Aqueous  Liquids. — i.  Water  (Aqua). — A  weak  aqueous  solu- 
tion of  one  or  more  volatile  substances  (e.  g.,  peppermint  or  cin- 
namon water,  chlorine  water). 


40  PHARMACOLOGY   AND    THERAPEUTICS 

2.  Solution  (Liquor). — An  aqueous  solution  of  one  or  more 
non-volatile  chemic  substances  (Fowler's  solution). 

j.  Mixture  (Mistura). — An  aqueous  liquid  containing  in- 
soluble material  (rhubarb  and  soda  mixture).  It  requires  the 
label,  "Shake  before  using." 

4.  Syrup  (Syrupus). — A  dense  aqueous  solution  of  sugar  with 
or  without  medicinal  or  flavoring  substances  (syrup  of  ipecac) . 

5.  Mucilage    (Mucilago). — An    adhesive    aqueous   liquid    or 
paste  made  with  gum  (liquid — acacia;  paste — tragacanth). 

6.  Infusion   (Infusum). — A  liquid  obtained  by  steeping  a 
vegetable  drug  in  water  and  then  straining.    The  water  may  be 
cold,  warm,  or  hot,  but  the  drug  is  not  subjected  to  boiling. 

7.  Decoction  (Decoctum). — A  liquid  made  by  boiling  a  vege- 
table drug  with  water,  then  straining. 

8.  Juice  (Succus). — The  juice  expressed  from  parts  of  fresh 
plants  ("fresh"  meaning  "undried") ;  an  example  is  limonis  succus 
(lemon-juice).    Alcohol  may  be  added  as  a  preservative. 

Alcoholic  Liquids. — i.  Fluidextract  (Fluidextractum). — An 
alcoholic  or  hydro-alcoholic  liquid  preparation  made  by  extrac- 
tion, and  representing  the  drug  volume  for  weight;  i.  e.,  i  c.c. 
of  the  fluidextract  represents  the  strength  of  i  gram  of  the  drug. 

2.  Tincture  (Tinctura). — An  alcoholic  or  hydro-alcoholic 
liquid  preparation  made  by  extraction  and  of  a  strength  less  than 
that  of  the  drug;  i.  e.,  tinctures  are  of  the  same  nature  as  fluid- 
extracts,  but  weaker.  A  few  simple  alcoholic  solutions  are  in- 
correctly called  tinctures,  e.  g.,  tincture  of  ferric  chloride,  tincture 
of  iodine. 

j.  Elixir  (Elixir). — A  sweetened,  aromatic,  hydro-alcoholic 
liquid  (aromatic  elixir). 

4.  Spirit  (Spiritus). — A  simple  solution  of  one  or  more  volatile 
substances  in  alcohol  (spirit  of  chloroform). 

5.  Wine  (Vinum). — The  wines  are  not  now  official.    They  are 
made  like  a  tincture  or  solution,  but  with  white  wine  and  alcohol 
as  the  menstruum  (bitter  wine  of  iron). 

Miscellaneous  Liquids. — /.  Vinegar  (Acetum). — Made  like 
a  tincture,  but  with  diluted  acetic  acid  as  the  menstruum  (the 
vinegar  of  squill  is  the  only  one  official). 

2.  Emulsion  (Emulsum). — A  milk-like  preparation  in  which 
an  oil  or  resin  is  finely  divided  and  rendered  miscible  with  water 
by  means  of  some  viscous  or  adhesive  substance.  Emulsions 
are:  (a)  Natural,  as  in  egg-yolk  and  milk.  (/>)  Gum  resin,  as  in 
emulsum  asafcctidse;  the  drug  contains  gum,  oil  and  resin,  and 
on  rubbing  with  water  makes  an  emulsion,  (c)  Artificial,  in 
which  the  adhesive  must  be  added,  as  emulsion  of  cod-liver 
oil. 


PHARMACEUTIC    PREPARATIONS  41 

j.  Honey  (Mel). — A  liquid  or  semiliquid  mixture  of  a  drug 
with  honey  (honey  of  rose). 

4.  Oleoresin  (Oleoresina) . — A  semiliquid  ethereal  extract  of 
a  drug  which  contains  oil  and  resin.    The  oleoresin  contains  the 
ether-soluble  constituents  of  the  drug,  the  ether  being  evaporated 
off.    It  is  of  greater  strength  than  the  drug  itself  (oleoresin  of 
male  fern). 

5.  Glycerite  (Glyceritum). — A  liquid  or  semisolid  solution  in 
glycerin  (glycerite  of  boroglycerin) . 

6.  Liniment  (Linimentum) . — An  oily  or  alcoholic  solution  or 
mixture  to  be  applied  to  the  skin  (liniment  of  camphor) . 

7.  Lotion. — An  aqueous  liquid  for  application  to  the  skin. 
There  are  no  official  lotions. 

8.  Collodion  (Collodium). — A  solution  of  a  medicinal  sub- 
stance in  collodion  (cantharidal  collodion). 

Solids  and  Semisolids. — i.  Extract  (Extractum). — A  prepa- 
ration of  dry  or  plastic  consistence,  made  by  extracting  a  drug 
with  a  solvent,  and  then  removing  the  solvent  by  evaporation. 
An  extract  is  of  greater  strength  than  the  crude  drug.  Most 
extracts  are  about  4  or  5  times  as  strong  as  the  drug  from  which 
they  are  made  (extract  of  belladonna). 

2.  Powder  (Pulvis). — A  dry  powdery  mixture  of  drugs  (pow- 
der of  ipecac  and  opium) . 

3.  Trituration  (Trituratio). — A  powdery  mixture  of  a  drug 
with  sugar  of  milk.     The  only  official  trituration  is  trituratio 
elaterini,  of  10  per  cent,  strength. 

4.  Mass  (Massa). — A  plastic  mixture  for  division  into  a  num- 
ber of  equal  objects,  such  as  pills,  troches,  etc.,  and  usually  ob- 
tained by  incorporating  drugs  with  an  adhesive  substance. 

5.  Pill  (Pilula). — A  rounded  or  oval  body  of  size  to  be  readily 
swallowed,  and  made  of  cohesive  drugs  or  drugs  incorporated 
with  an  adhesive  substance.     Pills  may  be  coated  with  sugar, 
gelatin,  silver,  keratin,  or  salol.    The  coating  may  be  white,  pink, 
chocolate-colored,  etc.  t 

6.  Troche  (Trochiscus). — A    flat  body,  rounded  or  lozenge 
shaped,  intended  to  be  dissolved  slowly  in  the  mouth.    It  contains 
the  medicinal  substance,  and  in  addition  sugar,  flavoring  and 
adhesive  material  (troches  of  ammonium  chloride). 

7.  Compressed    Tablet   (Tabella    compressa). — A  solid   body 
made  by  the  compression  of  a  powdered  drug  or  mixture  of  drugs 
in  a  suitable  mold.    With  insoluble  powders  the  hard  compres- 
sion retards  disintegration. 

8.  Tablet  Triturate  (Tabella  triturata). — A  solid  body  made 
of  drugs  triturated  with  sugar  of  milk,  and  molded  with  the  aid  of 
moisture.    It  disintegrates  as  the  sugar  of  milk  dissolves. 


42  PHARMACOLOGY   AND   THERAPEUTICS 

Q.  Confection  (Confectio). — A  pleasant-tasting  preparation 
made  by  mixing  medicinal  powders  and  aromatics  with  syrup 
or  honey  (confection  of  senna). 

10.  Granular  Effervescent  Salt  (Sal  Granulatus  Eff ervescens) . 
— A  preparation  made  by  adding  sodium  bicarbonate  and  citric 
or  tartaric  acid  to  the  drug,  moistening  with  alcohol,  and  passing 
through  a  coarse  sieve  to  form  granules.    It  is  added  to  water  and 
drunk  during  or  just  after  the  effervescence  (effervescent  sodium 
phosphate). 

11.  Paper  (Charta). — A  sheet  of  paper  impregnated  with  a 
medicinal  substance  (niter  paper) ,  or  bearing  it  in  a  state  of  fine 
subdivision  (mustard  paper).    There  are  none  official. 

12.  Plaster  (Emplastrum) . — A  solid  mixture  which  becomes 
plastic  and  adhesive  on  warming;  it  is  spread  in  a  thin  layer  over 
muslin,  moleskin,  etc.,  for  application  to  the  skin  (emplastrum 
belladonna?) . 

ij.  Poultice  (Cataplasma). — A  soft,  usually  hot  and  moist 
paste  for  external  application,  as  a  flaxseed  poultice. 

14.  Ointment  (Unguentum). — A  soft,  fatty  (unctuous)  prep- 
aration which  on  rubbing  melts  at  or  about  the  temperature  of 
the  body. 

15.  Cerate  (Ceratum). — An  unctuous  mixture  of  firmer  con- 
sistence and  higher  melting-point  than  an  ointment  (ceratum 
cantharidis). 

16.  Oleate  (Oleatum). — A  semisolid  solution  of  metallic  salts 
or  alkaloids  in  oleic  acid.     It  is  for  external  use  (oleatum  hy- 
drargyri). 

17.  Suppository  (Suppositorium). — A  solid  which  retains  its 
shape  at  normal  temperature,  but  readily  fuses  when  inserted 
into  a  body  orifice.    Suppositories  are  usually  made  with  a  basis 
of  cocoa-butter  and  are:    (a]   Rectal,  cone  shaped,  weight,  30 
grains  (2  gm.)  (b)  Urethral,  thin,  pencil  shaped,  weight,  30  to  60 
grains  (2  to  4  gm.)  (c)   Vaginal,  globular  or  elliptic,  weight,  60 
grains  (4  gm.).    Urethral  ajid  vaginal  suppositories  are  sometimes 
made  of  glycerinated  gelatin.     Small  rectal  suppositories  used 
for  children  and  in  irritative  conditions  of  the  anus  are  made 
about  15  grains  (i  gm.)  in  weight. 


WEIGHTS   AND   MEASURES 


43 


WEIGHTS    AND    MEASURES 

In  the  metric  system  the  liter  is  a  unit  of  capacity  equivalent  to  the  volume 
occupied  by  the  mass  of  i  kilogram  of  pure  water  at  its  maximum  density.  It  is 
equivalent  in  volume  to  1.000027  cubic  decimeter.  Under  this  definition  a  milli- 
liter  (o.ooi  of  a  liter)  is  different  from  a  cubic  centimeter  by  a  very  minute  frac- 
tion. However,  as  cubic  centimeter  is  the  term  used  throughout  medical  literature 
we  shall  use  it  in  this  book,  though  both  the  U.  S.  and  British  Pharmacopoeias  have 
adopted  the  term  milliliter  (mil)  in  its  place. 

A.  Metric 

A  pproximate 
Weight  Written  Equivalent 

i  milligram  (mg.) o.ooi  ^  grain 

10  milligrams  =  i  centigram  (eg.) o.oi  £  grain 

10  centigrams  =  i  decigram  (dg.) o.i  if  grains 

10  decigrams  =  i  gram  (gm.) i.o  15  grains 

1000  grams  =  i  kilogram  (kilo.) 1000.0  2\  pounds 

Volume 

i  milliliter  (mil.) i.o  15  minims 

i  cubic  centimeter  (c.c.) i.o  15  minims 

(i  c.c.  of  water  weighs  i  gm.) 

1000  cubic  centimeters  =  i  liter  (L.) 1000.0  34  fluidounces 

Length 

i  millimeter  (mm.) -^  inch 

10  millimeters  =  i  centimeter  (cm.) ?  inch 

10  centimeters  =  i  decimeter  (dm.) 4  inches 

10  decimeters  =  i  meter  (M.) 40  inches 

B.  Apothecaries 

Approximate 
Weight  (Troy  Weight)  Equivalent 

i  grain  (gr.) 0.065  gm. 

10  grains 0.7  gm. 

20  grains  =  i  scruple  O) 1.3  gm. 

3  scruples  =  i  dram  (5) 4.0      gm. 

8  drams  =  i  ounce  (3) 30.0  gm. 

12  ounces  =  i  pound  (ft>) 372.0  gm. 

Volume 

1  minim  (rrj) 0.06    c.c. 

60  minims  =  i  dram  (5) 4.0      c.c. 

8  drams  =  i  ounce  (5 ) 30.0  c.c 

16  ounces  =  i  pint  (O) 475-Q  c.c. 

2  pints  =  i  quart  (Oij) 95o.o  c.c. 

8  pints  =  i  gallon  (Cong.). 

(i  gill  =  4  fluidounces.) 
Length 
i  inch  (in.) 2.5      cm. 

Noteworthy  Terms 

ounce  avoirdupois 437-5  grains 

ounce  troy 480.0  grains 

fluidounce  of  water  (the  standard  of  volume) 455-7  grains 

pound  avoirdupois  is 7000.0  grains 

pound  troy  is 5760.0  grains 

i  minim  of  water  weighs  45gQ7  grains  =  0.95  grain  =  61.61  mg. 

15  grains  of  water  =  16  minims;  one  grain  of  water  measures 

1.05  minims  =  0.0648  c.c. 
An  imperial  pint  is  20  ounces;  a  United  States  pint  is  16  ounces. 


44  PHARMACOLOGY   AND   THERAPEUTICS 

EXACT  EQUIVALENTS  OF  METRIC  AND  APOTHECARIES'  WEIGHTS 
AND  MEASURES  ACCORDING  TO  THE  U.  S.  PHARMACOPCEIA 

Volume 

c.c 16.23      minims 

liter  (1000  c.c.) 33.8        oz. 

minim  (115) 0.061  c.c. 

fluidram  (5) 3-696  c.c. 

fluidounce  (5) 29-57  c.c. 

pint  (O) .  .                473-i8  c.c. 

Weight 

i  milligram,  o.ooi  (mg.) 0.0154  grain 

i  centigram,  o.oi  (eg.) 0.1543  grain 

i  decigram,  o.i  (dg.) i-543    grains 

i  gram,  i.o  (gm.) iS-4324  grains 

30  grams,  30.0 462.9        grains 

3 1  grams 478.4        grains 

i  grain  (gr.) 0.065    gm- 

10  grains 0.648  gm. 

15  grains 0.972  gm. 

i  scruple 1.296  gm. 

i  dram  (5) 3-89  gm. 

i  ounce  troy  (5) 31-1  gm. 

i  ounce  avoirdupois 28.35  gm- 


ACTIVE   PRINCIPLES   AND   ASSAY  PROCESSES 

As  might  be  expected  from  the  different  conditions  under 
which  plants  grow,  the  different  methods  of  collecting,  drying, 
and  preserving  drugs,  the  effects  of  age  on  the  drug,  etc.,  crude 
drugs  vary  in  strength.  On  this  account  the  use  of  active  con- 
stituents by  themselves  has  much  to  commend  it,  e.  g.,  quinine 
in  preference  to  cinchona,  strychnine  in  preference  to  nux  vomica, 
resin  of  podophyllum  in  preference  to  podophyllum.  These  sub- 
stances tend  also  to  be  more  readily  absorbed  when  thus  separated 
from  the  extractive  matter  of  the  crude  drug.  But  in  many 
instances  it  is  impossible  or  too  expensive  to  isolate  the  active 
ingredients  in  pure  form,  or  there  is  a  preference  for  the  combi- 
nations or  mixtures  as  they  occur  in  nature,  so  pharmaceutic 
preparations,  and  even  the  powdered  crude  drugs,  are  much 
prescribed,  even  though  their  active  principles  are  available. 

This  being  the  case,  it  is  a  matter  of  great  importance  that  some 
of  the  more  potent  of  these  drugs  and  preparations  are  standard- 
ized by  the  Pharmacopoeia  to  contain  a  definite  percentage  of  the 
active  ingredients.  For  instance,  when  assayed  by  the  process 
specified  in  the  Pharmacopoeia,  nux  vomica  must  yield  not  less 
than  2.5  percent,  of  alkaloid;  jalap,  not  less  than  8  per  cent, 
of  resin;  the  tincture  of  opium,  1.2  to  1.25  per  cent,  of  morphine. 
These  are  known  as  assayed  drugs  or  preparations. 

An  assay  process  is  a  process  by  which  the  strength  of  a  sub- 


THE   PHARMACOPCEIA  45 

stance  or  preparation  is  determined.  There  are  three  kinds  of 
assay  processes  for  drug  preparations,  viz.,  volumetric,  gravimet- 
ric, and  biologic  or  physiologic.  The  last-named  type  of  assay 
has  been  devised  for  some  of  the  drugs  whose  active  principles 
are  not  readily  isolated.  For  digitalis,  for  example,  one  assay 
process  ascertains  the  amount  of  digitalis  necessary  to  bring  into 
systolic  standstill  the  heart  of  a  frog  of  definite  weight  and  of  a 
certain  species  and  sex. 

THE   PHARMACOPCEIA 

The  Pharmacopoeia  is  a  book  which  defines  and  standardizes 
certain  drugs  and  their  preparations.  Its  aim  is  to  establish 
definiteness  for  a  selected  number  of  those  in  extensive  use  by 
physicians.  A  number  of  the  more  enlightened  nations  have 
pharmacopeias,  so  there  are  the  British  Pharmacopoeia,  the 
German,  the  Swiss,  the  Japanese,  etc.  For  us,  "The  Pharma- 
copoeia" is  the  United  States  Pharmacopoeia  (written  "U.  S.  P."). 
Its  drugs  and  preparations  are  spoken  of  as  official.  By  the  Pure 
Food  and  Drugs  Act  the  National  Formulary  preparations  have 
also  official  recognition.  The  official  preparations  are,  therefore, 
the  ones  that  are  standardized;  hence  they  are  the  preparations 
that  can  be  obtained  of  uniform  strength  throughout  the  United 
States;  and  they  are,  for  the  most  part,  the  forms  in  which  reme- 
dies can  be  readily  supplied  by  the  pharmacist.  Hence,  the 
official  preparations  are  the  forms  to  be  preferred  by  the  physician 
in  prescribing. 

To  illustrate  the  character  of  the  Pharmacopoeia,  take  the 
drug  strophanthus  and  its  tincture.  "Strophanthus"  is  defined 
as  ''the  dried  ripe  seeds  of  Strophanthus  Kombe  and  of  5.  hispidus, 
deprived  of  their  long  awns."  The  seeds  of  other  species  of 
strophanthus  can  be  procured,  but  the  pharmacist  must  not 
employ  any  but  those  of  the  species  mentioned,  and  he  must 
first  remove  the  long  awn,  a  spear-like  projection  at  the  apex  of 
the  seed  which  contains  none  of  the  medicinal  ingredient.  Fur- 
thermore it  must  respond  to  the  requirements  of  a  biologic  assay 
on  frogs,  as  given  in  the  Pharmacopoeia. 

For  the  tincture  of  strophanthus  the  Pharmacopoeia  directs 
that  10  grams  of  strophanthus  shall  be  taken  to  make  100  c.c.  of 
the  tincture,  i.  e.,  it  shall  be  of  10  per  cent,  strength,  it  must  be 
made  with  a  certain  specified  menstruum,  and  it  must  have  a 
certain  physiologic  activity.  Therefore,  when  the  tincture  of 
strophanthus  is  prescribed,  since  it  is  an  official  preparation,  the 
pharmacist  is  not  entitled  to  dispense  a  tincture  of  any  other 
strength  or  method  of  manufacture.  On  the  other  hand,  if  a 


46  PHARMACOLOGY  AND  THERAPEUTICS 

physician  prescribes  an  unofficial  preparation,  the  pharmacist 
may  dispense  one  of  any  arbitrary  strength  and  made  by  any 
method  convenient,  and  the  physician  is  left  in  uncertainty  about 
what  his  patient  is  getting. 

The  United  States  Pharmacopoeia  gives  information,  also, 
about  specific  gravity,  melting-point,  solubilities,  tests  of  identity, 
tests  for  impurities  or  adulterants,  the  average  dose,  etc.  It  is, 
therefore,  an  official  formulary  and  book  of  standards,  and  is  a 
working  guide  and  dictator  for  the  supplier  of  drugs,  the  manu- 
facturer of  preparations,  and  the  pharmacist.  It  is  not  in  any 
sense  a  book  to  be  memorized  by  the  medical  student;  but  the 
choice  of  its  preparations  in  prescribing  favors  accurate  thera- 
peutics. 

The  Pharmacopoeia  is  controlled  and  published  by  the  Na- 
tional Pharmacopoeial  Convention,  a  gathering  of  delegates 
from  the  various  medical  and  pharmaceutic  colleges  and  state 
and  national  societies,  and  certain  other  selected  societies,  and 
from  the  Army,  Navy,  and  Marine-Hospital  Service.  This  Re- 
vision Convention  meets  every  ten  years  (1890,  1900,  1910, 
etc.)  at  Washington,  D.  C.,  to  determine  the  principles  to  govern 
the  next  revision.  It  also  appoints  a  Committee  of  Revision  to 
carry  out  the  details  of  the  revision,  and  administrative  officers 
to  issue  the  new  edition  when  it  is  ready.  Three  or  four  years  are 
then  spent  by  the  Committee  of  Revision  in  research  and  in  the 
compilation  of  the  revised  book,  which  becomes  official  on  a  fixed 
date  after  it  is  issued.  It  is  known  as  the  Pharmacopoeia  of  1890 
or  1900,  etc.,  the  year  of  the  Pharmacopoeial  Convention.  The 
present  Pharmacopoeia  is  the  Pharmacopoeia  or  revision  of  1910; 
it  became  official  on  September  i,  1915.  If  a  physician  wishes  to 
prescribe  the  formula  of  a  previous  pharmacopoeia,  he  must 
specify  on  his  prescription,  "U.  S.  P.  1880,"  "U.  S.  P.  1890,"  etc. 

Because  it  recognizes  so  many  seemingly  needless  drugs  and 
preparations,  the  Pharmacopoeia  has  been  much  criticized.  But 
it  is  to  be  borne  in  mind  that  the  Pharmacopoeia  does  not  con- 
sider merely  the  usefulness  of  an  article,  but  attempts  to  stand- 
ardize those  drugs  and  preparations  which  are  in  extensive  use 
by  the  recognized  authorities  in  medicine  in  any  part  of  the 
country.  It  must  also  standardize  all  substances  used  in  making 
official  preparations,  whether  or  not  of  medicinal  value. 

The  National  Formulary  is  a  book  issued  by  the  American 
Pharmaceutical  Association,  with  the  idea  of  standardizing  some 
non-pharmacopeia!  preparations  that  are  in  common  use.  In  a 
prescription  the  letters  "X.  F.''  following  the  name  of  a  prepara- 
tion (c.  £.,  lotio  plumbi  et  opii,  X.  F.)  call  for  the  dispensing  of  a 
preparation  made  according  to  the  formula  of  this  book. 


DOSAGE  47 

A  dispensatory  is  a  commentary  on  drugs,  a  general  reference 
work  on  the  botany,  pharmacognosy,  chemistry,  pharmacy,  and 
therapeutics  of  drugs.  It  is  an  extensive  work  and  is  not  official. 
The  United  States,  the  National,  and  King's  Dispensatories  are 
the  best  kno\vn  in  this  country,  and  Hager's  Praxis  in  Germany. 
They  give  a  vast  amount  of  information,  and  are  encyclopedic 
in  character,  scarcely  a  known  drug  escaping  some  recognition. 

Useful  Drugs  is  a  small  book  issued  by  the  Council  on  Phar- 
macy and  Chemistry  of  the  American  Medical  Association.  It 
presents  a  brief  but  practical  discussion,  from  the  modern  view- 
point, of  the  properties,  pharmacologic  action,  therapeutic  uses 
and  dosage  of  a  list  of  drugs  of  approved  worth.  It  should  be  in 
the  hands  of  every  practitioner. 

DOSAGE 

When  we  say  the  dose  of  a  drug,  we  mean  the  therapeutic  dose 
for  an  adult,  i.  e.,  the  amount  ordinarily  required  to  produce  a 
medicinal  effect.  The  Pharmacopoeia  gives  the  average  thera- 
peutic dose,  and  for  convenience  this  is  the  dose  to  learn,  in  most 
instances. 

The  minimum  dose  is  the  smallest  capable  of  producing  a 
medicinal  effect — not  quite  so  small,  however,  as  two  drops  of 
the  ninth  dilution  of  the  homeopaths,  which  Oliver  Wendell 
Holmes  estimated  to  be  of  the  strength  of  one  drop  in  ten  billion 
gallons.  A  maximum  dose  is  the  greatest  dose  that  can  be  ad- 
ministered without  probability  of  poisonous  effects.  A  toxic  dose 
is  a  poisonous  dose. 

Remedies  are  administered  either  in  single  doses  or  in  repeated 
doses.  A  single  dose  of  a  medicine  may  be  given  all  at  once,  as 
two  compound  cathartic  pills  or  an  ounce  of  whisky;  or  in  divided 
doses,  as  when  one  grain  of  calomel  is  given  in  one-quarter  grain 
tablets,  one  every  half-hour  for  four  doses. 

Repeated  doses  may  be  intended  to  have  an  effect  just  at  the 
time  of  administration,  as  a  bitter  before  each  meal  to  improve 
the  appetite;  or  to  have  a  continuous  effect,  as  digitalis  for  a  dis- 
ordered heart.  To  produce  a  continuous  effect,  remedies  are 
usually  given  three  or  four  times  a  day,  for,  as  a  rule,  it  is  too 
great  trouble  for  patients  to  take  medicine  more  often  than  this. 
Even  very  sick  patients  should  not  be  disturbed  by  too  frequent 
medication. 

Sometimes  a  powerful  drug  given  for  continuous  effect  is 
administered  in  too  large  amounts  for  ready  secretion,  so  that  it 
accumulates  in  the  system  until  poisonous  symptoms  appear. 
Such  a  drug  is  known  as  a  cumulative  poison.  The  ill  effects  are 


48  PHARMACOLOGY  AND  THERAPEUTICS 

dependent  upon  the  failure  of  elimination  to  keep  pace  with  the 
ingestion  of  the  drug.  The  most  common  drugs  to  give  cumula- 
tive effects  are  digitalis,  arsenic,  mercury,  and  lead.  Lead  and 
arsenic,  indeed,  are  so  slowly  excreted  that  they  may  accumulate 
in  the  system  even  when  taken  only  in  the  minutest  quantities 
at  a  time,  as  from  drinking-water  that  has  lain  in  leaden  pipes, 
or  breathing  the  air  of  a  room  with  an  arsenic  color  in  the  wall- 
paper. 

The  phrase  "pushing  a  drug  to  its  physiologic  limit"  is  some- 
times employed  when  a  remedy  is  given  in  gradually  increasing 
doses  until  toxic  symptoms  begin  to  appear. 

FACTORS   WHICH   MODIFY   THE   DOSE 

It  must  be  apparent  that  the  ordinary  average  adult  dose  is 
not  the  dose  for  every  one  under  all  circumstances.  Some  of  the 
factors  modifying  the  dose  are: 

1.  Body  Weight. — In  pharmacologic   experimentation  it  is 
customary  to  estimate  the  dosage  in  proportion  to  the  weight  of 
the  animal.    Within  certain  limits  this  should  be  a  good  method 
with  humans,  and  it  is  the  basis  of  Clark's  rule,  which  assumes 
that  the  average  weight  of  an  adult  is  150  pounds.    The  rule  is — 

Adult  dose  X  ^!f0  .    But  a  patient  in  bed  cannot  be  weighed, 

and  it  takes  an  expert  to  guess  such  a  one's  weight  correctly;  and 
a  man  with  dropsy  or  an  adipose  patient  would  have  some  extra- 
neous weight  to  be  allowed  for.  So,  as  a  matter  of  fact,  either  on 
account  of  our  highly  organized  nervous  systems  or  on  account  of 
our  ways  of  eating  and  drinking  and  working,  or  for  other  reasons, 
the  rule  of  weight  does  not  seem  suitable  for  practical  use. 

2.  The  Age. — It  is  evident  that  the  dose  for  an  adult  is  not 
the  same  as  that  for  a  child.    Yet  to  establish  a  working  rule  is 
not  easy,  for  not  only  is  there  no  regular  increase  in  a  child's 
weight  according  to  age,  but  there  is  also  unequal  development 
of  the  different  systems  of  the  body.    The  weight  rule  would  be 
the  best  but  for  its  difficulty  of  adoption,  and  to  multiply  the 
adult  close  by  a  simple  fraction  with  the  child's  age  as  numerator 
and  the  supposed  earliest  adult  age  as  denominator,  will  not  be 
correct.     It  will  not  do,  for  example,  to  take  an  arbitrary  age  of 
twenty  or  twenty-four  as  the  adult  age,  and  take  one-twentieth 
or  one  twenty-fourth  for  each  year  of  the  child's  age.     The  fol- 
lowing table  of  the  average  weights  at  the  different  ages,  taken 
from  Bowditch's  statistics  in  8008  children  in  Boston,  and  Paster's 
of  14,744  children  in  St.  Louis,  as  recorded  by  Holt,  shows  how 
absurd  it  is  to  estimate  the  close  at  two  years  as  twice  that  at  one 
year,  etc.     The  figures  given  are  for  the  boys,  those  for  the  girls 


FACTORS   WHICH  MODIFY   THE   DOSE  49 

being  for  the  most  part  not  more  than  one  to  three  pounds 
different. 

Age  Weight 

Half  year 16.0  pounds 

One  year 2 1  .o 

Two  years 27.0 

Three  years 32.0 

Four  years 36.0 

Five  years 41.2 

Six  years 44.4 

Seven  years 48.6 

Eight  years 53.5 

Nine  years 58.7 

Ten  years 64.6 

Eleven  years 70.6 

Twelve  years 76.7 

Thirteen  years 83.7 

Fourteen  years 94.0 

Fifteen  years 107.3 

Sixteen  years 1 19.1 

From  these  figures  a  fairly  accurate  age-weight  rule  would  be: 
age  p  3  X  adult  dose.  In  other  words,  in  writing  for  30  doses 

(4  ounces  with  i  dram  dose)  put  down  as  many  minims  or  grains 
as  the  age  +  3;  in  writing  for  15  doses  (2  ounces  with  i  dram 
dose)  put  down  half  as  many  minims  or  grains  as  the  age  +  3. 
In  the  metric  system  put  down:  the  adult  dose  X  (age  +  3) 
X  3,  and  move  the  decimal  point  two  places  to  the  left. 
Two  other  rules  in  common  use  are  Young's  and  Cowling's: 

Young's  rule  is:   Adult  dose  X  ^,j^±~[2' 

r*       T      >    *      7      •         Aiiij  xx   a«e  at  next  birthday       T 

Cowlings  rule  is:  Adult  dose  X  -  — —  — .  In  pre- 
scribing by  this  rule,  all  that  is  necessary  is  to  write  for  24  doses 
and  set  down  for  each  ingredient  the  adult  dose  multiplied  by 
the  age  at  next  birthday. 

Fried' 's  rule  for  infants  under  one  year  is:  Adult  dose   X 

age  in  months 
150 

In  some  cases  these  rules  do  not  apply,  e.  g.,  children  react 
strongly  to  opium  and  other  narcotics,  while,  on  the  contrary, 
the  child's  dose  of  a  cathartic  or  belladonna  or  arsenic  approaches 
that  of  an  adult.  We  have  seen  the  same  amount  of  belladonna 
given  to  a  father  and  to  his  son  six  years  of  age  with  equal  effect; 
and  a  child  of  three  years  not  one  whit  more  affected  by  a  grain 
of  calomel  than  was  her  mother  by  half  the  dose.  On  the  other 
hand,  we  have  seen  a  child  of  one  year  "doped"  by  one-twentieth 
of  a  grain  of  powdered  opium. 

In  old  age  the  dose  must  be,  as  a  rule,  somewhat  less  than  in 
the  prime  of  life;  and  especially  must  skin  irritants,  irritant 


50  PHARMACOLOGY  AND  THERAPEUTICS 

cathartics,  narcotics,  and  depressant  drugs  be  used  with  cau- 
tion. 

3.  Sex. — Women  usually  require  smaller  doses  than  men, 
not  only  because  of  their  average  smaller  stature  and  quieter 
life,  but  also  because  of  their  greater  susceptibility  to  any  in- 
fluences.    During  menstruation  and  pregnancy  irritant  cathar- 
tics, and  during  lactation  saline  cathartics,  are  to  be  avoided  or 
used  with  caution. 

4.  Temperament,  Race,  Occupation.— The  patient  of  highly 
neurotic  temperament  is  more  susceptible  than  the  phlegmatic 
person.     Such  difference  may  be  racial,  the  excitable  Italian, 
for  example,  being  more  easily  affected  than  the  stolid  Swede; 
or  it  may  have  to  do  with  activity  and  occupation,  the  athlete 
or  the  man  who  works  all  day  out-of-dbors  and  is  inured  to  hard- 
ship being  less  readily  affected  than  the  man  of  sedentary  habits, 
the  merchant,  student,  or  artist. 

5.  Previous    Habits    (Toleration). — The    morphine    habitue 
can  take  with  impunity  a  dose  of  morphine  large  enough  to  poison 
one  not  habituated,  and  will  obtain  no  effect  from  the  ordinary 
dose.    An  old  toper  with  cirrhosis  of  the  liver  will  fail  to  get  a 
medicinal  effect  from  the  usual  dose  of  a  tablespoonful  of  whisky. 

6.  Idiosyncrasy    and    Susceptibility ,~  Idiosyncrasy   is    that 
condition  in  which  a  patient  develops  special  and  unusual  effects 
from  a  remedy  or  food.    Some  people  develop  a  rash  after  eating 
strawberries,   others  after  eating  lobster,   fish,   or  buckwheat. 
Sometimes  all  the  members  of  a  family  show  such  an  idiosyncrasy 
to  some  special  article  of  food,  and  it  is  manifest  in  successive 
generations.     The  same  is  true  of  drugs.    A  minute  amount  of 
cocaine  dropped  in  the  eye  or  applied  to  the  nasal  mucous  mem- 
brane may  cause  dangerous  symptoms  in  one  patient,  though 
cocaine  is  used  in  the  eyes  and  noses  of  thousands  of  other  pa- 
tients without  any  untoward  symptoms  at  all;  or  a  dose  of  anti- 
pyrine  may  be  followed  by  a  marked  rash,  which  recurs  each  time 
the  drug  is  taken.     These  are  unusual  and  unexpected  effects, 
and  depend  not  so  much  on  the  size  of  the  dose  as  upon  a  specific 
and  unusual  hypersusceptibility  of  the  patient  toward  the  drug. 

An  ordinary  increase  of  susceptibility  means  lowered  resistance 
— a  condition  in  which  the  usual  or  expected  effects  are  produced 
by  less  than  the  usual  amounts.  For  example,  two  or  three 
grains  of  quinine  sulphate  produce  in  some  people  the  ringing 
in  the  ears,  deafness,  and  headache  that  in  most  persons  do  not 
come  from  less  than  10  or  20  grains.  Diminished  susceptibility 
means  heightened  resistance,  the  patient  showing  the  usual 
effects,  but  only  after  larger  doses  than  usual.  For  example, 
some  persons  can  take  two  or  three  cups  of  coffee  and  then  sleep 


FACTORS    WHICH   MODIFY   THE   DOSE  51 

soundly,  though  this  is  enough  to  keep  the  average  person  wide 
awake  for  hours. 

7.  The  Nature  of  the  Disease. — In  great  pain,  as  in  peri- 
tonitis, morphine  may  be  borne  in  doses  that  would  ordinarily 
be  poisonous.    On  the  other  hand,  in  cyanosis  or  conditions  with 
bad  breathing,  morphine  should  be  used  with  caution  because  of 
its  tendency  to  depress  the  respiration.    In  malaria,  quinine  can 
be  borne  in  larger  doses  than  when  it  is  used  for  other  purposes. 

Again,  in  Bright's  disease  or  other  conditions  involving  the 
eliminating  organs  drugs  may  more  readily  accumulate  in  the 
system  and  cause  cumulative  poisoning;  and  in  functional  or 
organic  disturbance  of  the  liver  certain  substances,  like  phenol 
or  morphine,  may  have  a  more  pronounced  poisonous  effect  than 
otherwise. 

8.  The  Object  of  the  Medication. — Quinine  as  a  bitter  appe- 
tizer may  be  given  in  doses  of  one  or  two  grains,  while  quinine 
for  malaria  is  given  in  a  single  large  dose  of  15  or  20  grains,  fol- 
lowed by  5  grains  three  times  a  day  for  a  month.    In  a  cough 
mixture  for  a  child  syrup  of  ipecac  is  given  in  dose  of  2  to  5 
minims,  but  in  croup,  where  an  emetic  effect  is  desired,  a  whole 
teaspoonful  is  administered. 

It  is  to  be  noted  that  preparations  for  local  action  are  active 
according  to  their  percentage  strength  rather  than  according  to 
the  actual  amount  of  drug  employed. 

9.  The  Form  of  the  Remedy. — As  a  rule,  this  makes  but  little 
difference;  yet,  other  things  being  equal,  liquids  are  more  rapidly 
active  than  solids,   and  alcoholic  liquids  more  than  aqueous. 
Active  principles  are  more  rapid  than  crude  drugs,  powders  and 
dry-filled  capsules  than  pills,  fresh-made  pills  than  coated  pills. 
Some  cathartic  drugs,  like  aloes  and  cascara,  are  more  effective 
cathartics  than  their  active  principles.     This  is  because  of  the 
extractive  matter  present,  which  retards  absorption  and  keeps 
the  active  principles  in  the  alimentary  tract  until  they  reach  the 
colon. 

10.  The   Channel  of   Administration. — It  has  usually  been 
taught  that  the  hypodermatic  dose  should  be  half,  and  the  dose 
by  rectum  twice,  that  by  mouth.    In  a  number  of  instances,  how- 
ever, it  has  been  demonstrated  that  drugs  are  as  quickly  absorbed 
from  the  rectum  as  from  the  stomach,  or  even  more  quickly,  and 
also  that,  in  ordinary  circumstances,  most  drugs  are  absorbed 
from  the  stomach  or  duodenum  with  sufficient  rapidity  to  give  the 
full  effect  of  the  drug  in  a  short  time.    Therefore,  since  rectal  and 
hypodermatic  medication  are  resorted  to  only  under  special  cir- 
cumstances, their  dose  is  the  same  as  that  by  mouth.    In  rectal 
medication  the  strength  of  the  preparation  rather  than  the  total 


52  PHARMACOLOGY   AND   THERAPEUTICS 

dose  is  usually  desired,  for  the  rectum  is  seldom  resorted  to  for 
any  but  local  medication.  In  intravenous  medication  the  dose  is 
a  special  one  for  the  few  drugs  that  may  be  so  administered,  and 
is  usually  comparatively  small.  In  conditions  of  edema,  hypo- 
dermatic medicaments  may  be  retarded  in  their  absorption,  and 
in  congestive  conditions  of  the  stomach  and  bowels,  mouth 
doses  may  be  retarded. 

11.  The  Time  of  Administration. — After  meals  the  dose  is 
diluted  and  absorption  delayed  by  the  admixture  with  the  stom- 
ach contents;  so  if  a  rapid  effect  is  desired,  a  larger  dose  must  be 
given.     On  the  contrary,  the  empty  stomach  allows  immediate 
local  action  and  more  ready  absorption,  as  commonly  observed 
in  the  greater  activity  of  alcoholic  drinks  taken  before  meals. 

12.  The  Frequency  of  Administration. — It  goes  without  say- 
ing that  the  dose  of  a  powerful  drug  is  less  if  it  is  administered 
every  hour  or  two  than  if  given  three  times  a  day. 

ADMINISTRATION 

By  administration  is  meant  the  manner  in  which  the  remedy 
is  to  be  used.  Remedies  are  administered  to  obtain  either  a  direct 
local  action,  a  systemic  action,  or  a  remote  local  action. 

The  direct  local  action  is  the  action  at  the  place  at  which  the 
drug  is  applied,  as  on  the  skin,  or  in  nose,  throat,  stomach, 
urethra,  etc.  To  obtain  direct  local  action,  ointments,  lini- 
rnents,  plasters,  etc.,  are  employed.  Local  remedies  may  or  may 
not  require  to  be  absorbed.  Talcum  powder  applied  to  a  chafed 
skin,  or  bismuth  subnitrate  given  for  irritated  stomach  or  bowels, 
acts  by  coating  the  skin  or  mucous  membrane  and  is  not  absorbed; 
while  cocaine,  to  produce  a  local  anesthetic  effect,  must  be  ab- 
sorbed to  get  at  the  nerve-endings  or  nerves  beneath  the  epi- 
dermis. 

The  systemic  action  is  the  action  of  the  drug  after  its  absorp- 
tion into  the  circulation,  as  that  of  strychnine  on  the  spinal  cord, 
or  pilocarpine  on  the  nerve-endings  in  the  sweat-glands. 

The  remote  local  action  is  the  effect  of  the  drug  as  it  is  being 
excreted,  c.  £.,  the  irritation  of  the  bowels  by  mercuric  chloride 
as  it  is  passed  out  by  the  colon  glands,  or  the  antiseptic  action  of 
urotropine  as  it  is  eliminated  in  the  urine.  To  obtain  either  a 
systemic  action  or  a  remote  local  action  the  drug  must  be  ab- 
sorbed; that  is,  must  become  a  constituent  of  the  body  iluids. 


ADMINISTRATION  53 


THE  WAYS  IN  WHICH  DRUGS  MAY  BE  ADMINISTERED  FOR 
SYSTEMIC   AND   REMOTE  LOCAL  EFFECT 

A.  By  mouth,  the  usual  way,  the  drug  being  swallowed  and 
absorbed  into  the  sytem  from  the  alimentary  tract. 

B.  Subcutaneonsly  (hypodermatically) ,  the  drug  being  intro- 
duced beneath  the  skin  by  means  of  a  special  hollow  needle  and 
a  syringe.    To  be  used  thus,  a  preparation  must  be  in  liquid  form, 
and,  as  a  rule,  in  complete  solution;  though  in  some  instances, 
as  in  the  use  of  insoluble  mercury  salts,  the  drug  may  be  in  the 
form  of  a  fine  powder  held  in  suspension  in  oil.    A  substance  for 
hypodermatic  use  must  be  capable  of  complete  absorption,  or  it 
will  act  as  a  foreign  body;  and  must  be  in  small  quantity,  be- 
cause large  amounts  will  produce  too  great  separation  of  the 
tissues.     Irritant  drugs  are  only  occasionally  given  hypoder- 
matically, both  because  they  are  painful  and  because  they  may 
produce  necrosis  of  cells  with  abscess  formation.     Such  ab- 
scesses are  sterile,  however,  as  they  are  not  caused  by  pathogenic 
bacteria. 

For  convenience,  many  drugs  are  put  up  in  the  form  of  tab- 
lets called  hypodermic  tablets.  They  are  made  of  the  drug  and 
finely  powdered  cane-sugar  mixed  together,  moistened  with 
alcohol,  and  forced  into  molds.  When  dry,  they  can  be  handled 
without  disintegration,  but  are  readily  soluble.  (Tablets  made 
by  compression  do  not  dissolve  so  easily.)  Hypodermic  tablets 
of  salts  of  morphine,  atropine,  strychnine,  etc.,  can  be  carried  in 
a  pocket-case;  when  wanted,  they  may  be  placed  in  the  syringe 
and  dissolved  there  in  sterile  water  draw^n  up  to  make  the  solu- 
tion, or  may  be  made  into  a  solution  with  a  few  drops  of  water  in 
a  spoon.  For  sterilization  the  water  may  be  heated  in  a  spoon 
over  a  spirit-lamp  or  a  gas-burner.  Drugs  dissolved  in  normal 
salt  solution  (0.9  per  cent.  NaCl)  tend  to  be  less  irritant  to  the 
tissues  and  more  readily  absorbed  than  those  dissolved  in  plain 
water,  but  when  the  total  amount  of  the  solution  is  very  small, 
tap-water  will  do. 

To  give  a  hypodermatic  injection,  the  dose  is  placed  in  the 
hypodermic  syringe  (many  liquids  cannot  readily  be  drawn  up 
through  the  syringe  needle),  the  sterilized  needle  (it  may  be 
sterilized  in  a  test-tube  or  spoon)  is  screwed  on,  and  the  syringe 
is  turned  needle  upward  so  that  any  bubbles  of  air  may  be  driven 
out  by  pressure  on  the  piston.  Thin  liquids  may  be  drawn 
directly  into  the  syringe  through  the  needle. 

There  are  two  methods  of  injection  for  systemic  effect,  the 
subcutaneous  and  the  intramuscular.  In  the  subcutaneous  method 
the  properly  cleansed  skin,  usually  of  an  arm  or  a  leg,  is  pinched 


54  PHARMACOLOGY  AND  THERAPEUTICS 

up  between  the  thumb  and  finger  of  one  hand,  while  the  needle 
is  quickly  plunged  in  a  slanting  direction  through  the  skin  into  the 
subcutaneous  tissue.  In  the  intramuscular  method  the  needle  is 
plunged  straight  through  the  skin  and  subcutaneous  tissue  into 
the  underlying  muscle,  usually  in  the  back,  buttocks,  or  chest, 
though  sometimes  in  the  limbs.  This  method  favors  ready  ab- 
sorption. By  either  method,  a  sharp  needle  and  quick  puncture 
give  almost  no  pain.  The  fluid  is  slowly  injected,  the  needle  is 
quickly  withdrawn,  the  point  of  the  puncture  is  covered  to  pre- 
vent the  fluid  from  running  out,  and  the  spot  is  gently  massaged 
to  promote  diffusion  of  the  liquid  into  the  tissues.  The  hypoder- 
matic needle  may  be  cleansed  by  first  forcing  water  through  it, 
and  then  allowing  a  few  drops  of  alcohol  to  descend  through  it 
by  capillarity.  A  fine  wire  drawn  through  the  lumen  keeps  it 
permeable.  (In  the  introduction  of  cocaine  and  similar  drugs 
for  local  anesthesia  where  a  local  action  only  is  desired,  the  needle 
is  inserted  just  beneath  the  epidermis  and  gives  a  superficial 
subcutaneous  injection,  or  an  intracutaneous  injection.  This 
method  is  not  used  when  a  systemic  effect  is  desired.) 

There  are  certain  advantages  and  disadvantages  in  hypo- 
dermatic medication. 

The  advantages  are: 

j.  Certainty  of  action — all  the  drug  gets  into  the  tissues; 
therefore  the  dose  is  more  definite. 

2.  Rapidity  of  action — because  the  drug  in  most  instances 

quickly  reaches  the  circulation  by  means  of  the  capil- 
laries or  lymphatics. 

3.  Availability — when  administration  by  mouth  is  not  feasible, 

as  when  (i)  the  patient  cannot  swallow,  as  in  uncon- 
sciousness; or  (2)  will  not  swallow,  as  in  drunkenness 
or  delirium — or  when  drugs  are  taken  with  suicidal 
intent;  or  (3)  the  alimentary  tract  is  in  a  state  of  in- 
tolerance and  non-absorption,  as  in  uncontrollable  vom- 
iting or  diarrhea. 
The  disadvantages  are  seldom  encountered.  They  are: 

1.  The  chance  of  abscess  formation,  either  a  sterile  abscess 

from  an  irritant  drug,  or  an  infective  abscess  from  un- 
sterile  solution,  needle,  or  skin. 

2.  The  chance  of  injecting  the  drug  into  a  vein.    This  would 

plunge  the  whole  dose  into  the  circulation  at  once,  per- 
haps with  disastrous  results.  To  avoid  this  the  syringe 
may  be  unscrewed  from  the  needle;  if  blood  oozes  from 
the  needle,  this  is  withdrawn  and  inserted  elsewhere. 

3.  The  chance  of  injecting  the  drug  into  a  nerve,  with  result- 

ing great  pain  and  even  paralysis. 


ADMINISTRATION  55 

Hypodermatic  medication  has  a  very  restricted  employment, 
because  only  those  drugs  whose  dose  in  solution  is  of  small  bulk 
are  available  for  this  method  of  administration. 

C.  By  hypodermatoclysis,  in  which  a  large  quantity  of  saline 
liquid  (50  to  1200  c.c.)  is  injected  into  the  loose  tissues  about  the 
breasts  or  abdomen,  or  into  the  back  below  the  scapula,  or  into 
the  buttocks  or  thighs.    The  liquid  is  allowed  to  run  in  slowly  by 
means  of  a  funnel  or  reservoir  and  rubber  tube  attachment  to 
the  needle.     If  the  fluid  is  not  isotonic,  or  nearly  so,  with  the 
blood,  or  if  it  interferes  by  pressure  with  the  circulation  of  the 
part,  it  may  result  in  gangrene  or  abscess.    The  writer  has  seen 
extensive  gangrene  follow  the  injection  of  200  c.c.  of  2  per  cent, 
solution  of  sodium  carbonate  in  a  diabetic. 

D.  By  rectum. — Drugs  may  be  placed  in  the  rectum  by  means 
of  an  enema,  i.  e.,  a  rectal  injection,  or  in  the  form  of  a  supposi- 
tory or  ointment.    The  uncertainty  of  absorption  and  the  chance 
that  the  drug  will  be  expelled  limit  the  usefulness  of  this  channel 
and  largely  restrict  it  to  drugs  for  local  effect  only.    Proctoclysis 
is  a  rectal  irrigation  or  injection  intended  for  both  local  and 
systemic  effect.     It  is  usually  made  with  saline  or  medicated 
saline  fluids.     (See  Rectal  Treatment,  Part  II.) 

E.  By  the  skin,  by  inunction,  in  which  an  oily  or  fatty  prep- 
aration is  rubbed  upon  the  skin  and  left  to  be  absorbed.     On 
account  of  uncertainty  of  absorption  the  dose  may  vary  within 
wide  limits.    Mercurial  ointment  is  so  used  in  the  treatment  of 
syphilis,  and  cod-liver  oil  and  cocoa-butter  in  the  treatment  of 
malnutrition. 

F.  By  the  veins,  intravenous  medication. — Drugs  administered 
by  a  vein  act  with  great  promptness,  the  whole  dose  passing  at 
once  into  the  circulation.     Intravenous  medication  may  be  by 
injection  or  by  infusion.     In  intravenous  injection  the  drug,  di- 
luted with  a  small  quantity  of  normal  salt  solution,  is  injected 
from  a  syringe,  the  needle  being  plunged  through  the  wall  of  the 
vein  in  a  slanting  direction  and  toward  the  heart.     When  the 
needle  is  withdrawn,  the  valve-like  opening  thus  made  usually 
closes  of  itself,  though  sometimes  there  is  a  moderate  extrava- 
sation of  blood  into  the  tissues.    In  intravenous  infusion  a  large 
quantity  of  warm  normal  saline  solution  (500  to  1500  c.c.),  or 
some  isotonic  liquid,  with  or  without  the  addition  of  drugs,  is 
slowly  passed  into  the  vein  through  a  suitable  nozzle.     This  re- 
quires tying  a  vein,  so  it  cannot  be  repeated  more  than  once  or 
twice,  and  is  employed  only  in  emergencies. 

G.  Through  the  lungs  by  inhalation — of  gas  for  absorption  into 
the  system,  as  in  the  use  of  chloroform  or  ether  as  a  general 


56  PHARMACOLOGY   AND   THERAPEUTICS 

anesthetic.      (Inhalations   of  medicated   vapors  are  employed 
also  for  a  local  effect  on  the  respiratory  organs.) 


THE   TIME   OF  ADMINISTRATION 

This  is  of  some  importance,  e.  g.,  the  saline  cathartics  act 
most  rapidly  after  a  period  of  fasting,  so  are  usually  adminis- 
tered before  breakfast.  Irritant  drugs,  as  arsenic  or  iron  or  digi- 
talis, are  best  given  after  meals,  when  they  become  well  diluted 
with  the  stomach  contents,  and  come  very  little  in  contact  with 
the  stomach-wall  to  irritate  it.  Quinine  sulphate  is  given  after 
meals  not  only  because  it  is  irritant,  but  so  that  it  may  be  dis- 
solved by  the  acid  gastric  juice;  otherwise  its  absorption  is  re- 
tarded or  may  not  take  place  at  all.  Sleep  producers  are  most 
effective  at  the  natural  time  of  sleeping,  and  when  the  surround- 
ings are  favorable  to  sleep;  they  may  have  no  effect  at  all  if  the 
patient  is  up  and  about.  Sodium  bicarbonate  given  on  an  empty 
stomach,  i.  e.,  before  a  meal,  is  absorbed  as  sodium  bicarbonate, 
and  furnishes  alkali  directly  to  the  blood ;  but  if  it  is  given  during 
the  digestive  period,  it  neutralizes  the  hydrochloric  acid  of  the 
gastric  juice,  is  changed  to  sodium  chloride,  and  sets  free  carbon 
dioxide.  Appetizers  must  be  given  just  preceding  the  meal. 

SITES   AND   MODES   OF  ACTION   OF  DRUGS 

Drugs  may  act  as  such: 

1.  Independently  of  the  human  body,  as  antiseptics  on  micro- 
organisms in  disinfection. 

2.  In  or  about  the  human  body,  but  not  on  its  structures,  as  in 
the  destruction  of  a  tape-worm,  skin  parasites,  etc.,  or  as  in  the 
neutralization  of  a  hyperacid  gastric  juice  by  an  alkali. 

j.  On  the  structures  of  the  human  body.  Drugs  may  act  on 
the  tissues — (a)  Through  their  physical  or  mechanical  properties, 
as  when  cold  cream  is  applied  to  a  chapped  face  to  soften  the 
epithelium  and  prevent  its  drying;  or  when  bismuth  subnitrate, 
given  for  diarrhea,  coats  the  mucous  membrane  of  the  bowel 
and  soothes  and  protects  it.  Or  they  may  act  (b)  by  their  chcmic 
affinity  for  one  or  other  constituent  of  protoplasm,  so  that  either 
the  functional  power  of  the  cell  or  the  actual  cell  structure  is 
changed.  Some  of  these  are  general  in  their  action,  affecting 
practically  all  forms  of  protoplasm  (though  not  all  forms  to  a  like 
degree),  and  when  the  action  of  these  drugs  is  powerful,  they  are 
known  as  general  protoplasm  poisons.  Such  are  alcohol,  chloral 
hydrate,  and  quinine.  Other  drugs  are  selective,  exerting  their 
influence  only  on  special  groups  of  cells  and  having  no  effect 


SYNERGISTS   AND  ANTAGONISTS  57 

upon  the  vast  majority  of  body  structures.  This  is  presumably 
owing  to  a  chemic  affinity  for  some  component  of  the  cell.  Such 
drugs  are  strychnine,  which  has  a  selective  affinity  for  certain 
portions  of  the  central  nervous  system,  and  pilocarpine,  which 
has  an  affinity  for  secretory  nerve-endings. 

The  effect  of  drugs  on  cells  is  to  stimulate  them,  to  depress 
them,  or  to  change  and  destroy  them.  Stimulation  is  an  effect 
on  cells  by  which  their  power  or  their  readiness  to  functionate 
is  increased.  Depression  is  an  effect  on  cells  by  which  their 
power  or  readiness  to  functionate  is  lessened.  Paralysis  is  the 
cessation  of  the  power  to  functionate. 

Irritation  implies  an  anatomic  rather  than  a  functional  effect, 
tending  toward  the  harmful.  It  has  to  do  with  actual  changes 
in  the  cell  structure.  In  its  mild  degrees  irritation  may  have  the 
effect  of  stimulation;  in  stronger  forms  irritation  may  overwhelm 
the  cells  and  have  the  effect  of  depression;  while  excessive  or 
continued  irritation  induces  inflammation  and  even  actual  death 
of  the  cells  involved.  As  an  example,  take  cantharides,  an  irritant 
to  the  kidney  cells;  from  small  doses  the  cells  are  made  to  func- 
tionate more  actively,  and  increased  urination  takes  place,  but 
from  toxic  amounts  the  irritation  results  in  inflammation,  so 
that  nephritis  sets  in,  with  destruction  of  cells,  impairment  of 
function,  and,  perhaps,  suppression  of  the  urine. 

By  exhaustion  from  overwork,  continued  stimulation  may  re- 
sult in  depression  or  even  complete  cessation  of  the  work  of  the 
cells,  but  this  is  a  functional  inactivity  from  fatigue,  and  a  period 
of  rest  and  nutrition  will  usually  restore  the  cells'  power. 

Often  a  drug  will  be  found  to  stimulate  one  structure  and 
depress  another,  as  atropine,  which  stimulates  the  vagus  center 
and  depresses  the  vagus  endings;  or  pilocarpine,  which  stimu- 
lates the  nerve-endings  in  the  sweat-glands  and  tends  to  depress 
heart  muscle. 

SYNERGISTS   AND    ANTAGONISTS 

As  might  be  surmised,  the  same  dose  of  a  drug  will  exert  its 
usual  form  of  activity  more  easily  if  given  with  other  drugs  of 
the  same  class;  and  sometimes  a  combination  of  two  similar 
drugs  will  gain  a  result  that  one  alone  will  not  give  in  any  dose. 
Drugs  which  help  each  other  in  this  way  are  known  as  syner gists, 
or  mutual  helpers,  and  examples  are  bromides  and  chloral  hydrate 
for  sleep,  calomel  and  jalap  for  catharsis. 

On  the  contrary,  a  drug  may  lose  part  or  all  of  its  power 
because  of  some  agent  that  has  the  opposite  physiologic  effect. 
Such  opposing  agents  are  known  as  antagonists.  An  antagonist 
may  be  a  drug,  or  it  may  be  a  substance  formed  in  the  body,  as 


58  PHARMACOLOGY  AND  THERAPEUTICS 

epinephrine  or  thyroiodine  or  some  antitoxin.  The  antagonists 
may  act — (a)  on  the  same  structures — for  example,  bromides  pre- 
vent the  convulsions  of  strychnine,  both  acting  on  the  spinal 
cord;  caffeine  stimulates  the  psychic  and  motor  centers  of  the 
cerebrum,  while  alcohol  depresses  them;  pilocarpine  stimulates 
the  vagus  nerve-endings,  which  are  depressed  by  atropine;  (b) 
on  different  structures — for  instance,  digitalis  slows  the  heart  by 
stimulating  the  vagus  center,  while  atropine  prevents  this  effect 
by  depressing  the  vagus  nerve-endings;  adrenaline  stimulates 
the  nerve-endings  in  arterial  muscle,  causing  contraction  of  the 
arteries,  and  this  effect  can  be  wholly  neutralized  by  nitrogly- 
cerin,  which  depresses  the  arterial  muscle  itself. 

Incompatibility  should  not  be  confused  with  antagonism.  It 
is  a  pharmaceutic  term,  and  should  be  confined  to  prescriptions. 
Incompatibility  may  be  said  to  exist  between  two  substances 
when  their  admixture  in  a  prescription  results  in  chemic  or  phys- 
ical change  (other  than  mere  solution).  Examples  are  the  pre- 
cipitation when  strychnine  sulphate  in  solution  comes  in  contact 
with  tannic  acid,  or  when  lead  acetate  solution  is  mixed  with  a 
solution  of  alum.  Such  a  change  may  or  may  not  be  desired  in 
a  prescription;  hence  the  physician  should  know  what  changes 
may  take  place  in  substances  likely  to  be  prescribed  together. 
(See  Chapter  on  Prescriptions.) 

SCIENTIFIC   AND   EMPIRIC   THERAPEUTICS— ANIMAL 
EXPERIMENTATION 

Besides  the  constituents,  the  preparations,  and  the  pharma- 
cology of  a  drug,  we  are  to  learn  its  therapeutics,  and  we  might 
ask  how  have  our  drugs  come  to  have  their  present  uses  in 
medicine? 

From  the  employment  of  hepatica  for  liver  diseases  because 
its  leaf  suggested  the  liver,  to  the  employment  of  drugs  because 
of  known  actions  determined  by  animal  experimentation  and 
therapeutic  tests  is  a  far  cry,  yet  it  represents  only  a  few  years  of 
time,  and  indicates  the  rapid  strides  that  are  being  made  toward 
the  establishment  of  therapeutics  on  a  sound  scientific  basis. 
The  use  of  drugs  without  an  adequate  scientific  explanation  of 
their  efficiency  is  empiric.  For  instance,  colchicum  is  exten- 
sively employed  as  a  remedy  in  gout,  though  no  pharmacologic 
study  has  as  yet  indicated  how  or  why  colchicum  should  be  of 
benefit  in  this  disease.  We  give  it  in  gout  for  no  other  reason 
than  that  we  believe  that  it  has  worked  before;  in  other  words, 
we  use  it  empirically. 

As  a  matter  of  fact,  animal  experimentation  is  rapidly  rele- 


SCIENTIFIC   AND   EMPIRIC   THERAPEUTICS  59 

gating  empiric  remedies  to  the  realm  of  disuse  or  giving  them  new 
uses;  and  many  beliefs  in  the  efficacy  of  remedies  have  yielded 
to  the  adverse  proof  of  experiment.  Indeed,  very  few  of  the 
advances  of  the  last  half-century  could  have  been  made  but  for 
the  use  of  animals  in  the  study  of  the  action  of  drugs,  for  detailed 
experiments  on  human  beings  are  obviously  out  of  the  question. 
Anrep,  working  with  animals,  discovered  the  effects  of  cocaine 
as  a  local  anesthetic;  antipyrine,  phenacetin,  and  a  number  of 
so-called  coal-tar  products  owe  their  use  to  an  observation  by 
Filehne  that  antipyrine  reduced  the  temperature  of  animals 
put  into  fever  by  experimental  infection.  The  actions  of  nitrites, 
of  thyroid  extract,  of  saline  infusions,  of  diphtheria  antitoxin, 
etc.,  are  all  known  as  the  result  of  animal  experiments. 

In  this  connection  it  is  an  interesting  fact  that  many  of  the 
most  important  discoveries  have  resulted  from  purely  academic 
studies,  studies  made  without  thought  of  finding  substances 
useful  to  man.  For  example,  the  hypnotic  power  of  chloral 
hydrate  was  the  outcome  of  Liebreich's  attempt  to  solve  the 
purely  physiologic  question  as  to  whether  or  not  a  substance 
is  broken  up  into  its  constituent  parts  before  it  is  oxidized.  The 
sleep-producing  power  of  sulfonal  was  discovered  in  a  study  of 
the  effects  of  organic  sulphur  compounds  on  metabolism.  The 
power  of  epinephrine  to  constrict  the  arteries  and  raise  blood- 
pressure  was  first  noted  in  animal  experimentation  conducted 
with  no  thought  .of  therapeutic  possibilities.  And  the  recent 
wonderful  additions  to  our  knowledge  of  the  irregularities  of  the 
heart  may  be  attributed  largely  to  some  incidental  observations 
of  Cushny  and  others  while  performing  laboratory  experiments 
without  a  thought  of  their  ultimate  usefulness  to  man. 

These  illustrations  suggest  what  important  discoveries  might 
be  lost  to  us  if  animal  experimentation  were  to  be  undertaken  only 
with  the  definite  object  of  lessening  human  ills.  If  to  these  thera- 
peutic agents  which  we  owe  to  experiments  on  animals  we  add 
the  knowledge  of  the  body  processes,  of  disease  conditions, 
of  the  transmission  of  disease,  and  of  the  development  of  im- 
munity, it  makes  enormous  the  sum  of  the  obligations  of  medical 
science  and  human  sufferers  to  animal  experimentation,  com- 
monly known  as  vivisection.  Yet  in  recent  years  a  goodly 
number  of  people  who  profess  to  believe  that  no  animal  should 
be  sacrificed  for  the  good  of  human  beings,  have  made  the  most 
strenuous  efforts  to  bring  about  legislation  restricting  vivisec- 
tion. Their  harrowing  descriptions  of  experiments,  their  grossly 
exaggerated  statements  as  to  the  failure  of  experimenters  to 
protect  the  animals  from  pain,  and  as  to  the  brutality  of  the 
experimenters  themselves,  have,  unfortunately,  led  many  people 


60  PHARMACOLOGY   AND   THERAPEUTICS 

of  prominence  to  give  them  support,  and  have  made  it  incumbent 
upon  all  physicians  who  are  in  a  position  to  know  the  facts  to 
combat  in  every  way  this  retrograde  movement.  The  medical 
man,  of  all  persons,  is  in  the  best  position  to  realize  how,  in  the 
absence  of  vivisection  to  establish  exact  data,  every  attempt  to 
treat  the  sick,  especially  by  the  new  medical  graduate,  "would 
be  nothing  less  than  an  experiment  in  human  vivisection,  which 
animal  experimentation  now  renders  needless." 

THE   SCOPE   OF   TREATMENT 

Treatment  may  be  described  as  either  specific,  symptomatic, 
or  expectant. 

Specific  treatment  is  that  in  which  a  remedy  directly  attacks 
the  causative  factors  of  the  disease.  In  the  diseases  for  which 
such  specific  remedies  are  known  the  diagnosis  at  once  deter- 
mines the  remedy,  e.  g.,  in  diphtheria  the  remedy  is  diphtheria 
antitoxin;  in  acute  articular  rheumatism,  salicylic  acid;  in 
malaria,  quinine;  in  syphilis,  salvarsan  and  mercury.  In  each 
of  these  diseases  there  is  no  question  as  to  the  remedy,  for  it 
is  specific. 

But  for  almost  all  the  diseases  which  a  physician  is  called 
upon  to  treat,  such  as  tonsillitis,  typhoid  fever,  cirrhosis  of  the 
liver,  etc.,  there  is  no  specific  remedy,  so  that  he  is  forced  to  con- 
tent himself  with  attempts  to  combat  the  various  harmful  symp- 
toms and  their  effects  as  they  appear,  i.  e.,  he  employs  symp- 
tomatic treatment.  Thus  in  typhoid  fever,  if  there  is  constipation, 
a  drug  with  a  laxative  action  is  given;  if  diarrhea,  a  constipating 
drug;  if  there  is  a  weak  heart,  a  cardiac  stimulant  may  be  ad- 
ministered, and  if  the  heart  is  in  good  condition  it  needs  no  drug 
at  all.  Hence  in  many  cases  of  typhoid  fever  no  remedy  is  re- 
quired for  days  at  a  time,  for  none  of  the  manifestations  of  the 
disease  are  pronounced  enough  to  demand  special  antagonizing, 
and  we  know  of  no  remedy  that  will  cure  the  disease  itself. 
Again,  in  such  a  disease  as  cirrhosis  of  the  liver,  where  certain 
tissues  are  destroyed  and  cannot  by  any  known  means  be  re- 
stored, treatment  is  directed,  essentially,  to  combating  such 
symptoms  as  result  from  the  impairment  of  the  diseased  organ, 
and  perhaps,  also,  to  promoting  the  functional  power  of  such 
portions  of  the  organ  as  are  still  good.  These  are  conditions  for 
symptomatic  treatment.  In  fact,  almost  all  internal  treatment 
is  symptomatic  treatment,  and  it  is  because  of  this  fact  that  a 
knowledge  of  the  power  of  remedies  to  modify  the  structure  or 
functions  of  the  various  organs  of  the  body  is  so  important  to  the 
physician. 


HOW   MUCH   SHALL   WE    LEARN   ABOUT   DRUGS?  6 1 

Expectant  treatment  is  a  term  applied  to  the  administration 
of  mild  and  harmless  remedies  while  the  development  of  symp- 
toms is  awaited.  For  example,  if  one  sees  a  child  with  fever  but 
cannot  diagnosticate  the  disease  at  the  first  visit,  one  may  pre- 
scribe some  of  the  official  solution  of  ammonium  acetate,  which 
satisfies  the  patient  and  the  family,  tends  to  do  good,  does  no 
harm,  and  does  not  interfere  with  the  later  diagnosis  of  the 
disease.  Expectant  treatment  should  not  be  employed  if  its  neces- 
sity can  be  avoided.  A  remedy  employed  in  expectant  treatment 
is  known  as  a  placebo  ("I  placate  or  please"),  and  in  the  selec- 
tion of  a  placebo  it  is  well  to  choose  one  with  some  fitness  to  the 
case  in  hand,  as  the  spirit  of  mindererus  in  fever,  so  that  the 
tendency  will  be  good  even  though  its  power  is  slight.  In  neu- 
rotic conditions  a  placebo  is  often  administered  for  its  psychic 
effect. 

HOW   MUCH   SHALL   WE   LEARN   ABOUT   DRUGS? 

The  subject  of  the  materia  medica  is  an  extensive  one,  and  the 
text-books  contain  many  things  that  the  physician  does  not  need 
to  know.  He  need  not  learn  the  pharmacopeial  definition,  where 
and  how  a  drug  grows,  the  method  of  its  collection,  its  physical 
and  microscopic  characters,  its  preparation  for  the  market,  its 
adulterants,  the  process  of  manufacture  of  chemic  drugs,  the 
shapes  of  crystals,  melting-points,  etc.  Such  data  are  for  the 
pharmacist,  the  chemist,  and  the  pharmacognosist,  the  men 
upon  whom  the  physician  must  depend  for  his  proper  supply  of 
good  drugs. 

But  as  physicians  we  need  to  know  the  following: 

1.  The  English  and  Latin  names  of  drugs  and  their  prepara- 
tions.   In  prescriptions  we  use  the  Latin  names  only,  but  in  the 
literature  find  both  the  English  and  the  Latin,  so  we  must  know 
both.    We  learn,  therefore,  iha,tficus  is  fig,  and  zingiber  is  ginger, 
and  rhamnus  pursJiiana  is  cascara,  and  mistura  crctcE  is  chalk 
mixture.     (See  also  Use  of  Latin  in  chapters  on  Prescription- 
writing.) 

2.  The  Active  Constituents  of  Organic  Drugs. — Of  particular 
importance  are  those  active  constituents  which  are  isolated  from 
the  drug  and   used  by  themselves  in   medicine,  as   morphine, 
strychnine,  salicin,  menthol,  etc.,  or  those  which  make  unde- 
sirable incompatibles,  as  tannic  acid. 

j.  The  solubilities  and  incompatibilities  of  chemic  drugs  and 
of  active  constituents,  where  these  become  of  importance  from  a 
prescription  or  utility  point  of  view. 

4.  Preparations,  with  their  Strengths  and  Doses. — These  are 


62  PHARMACOLOGY   AND    THERAPEUTICS 

the  official  preparations,  and  such  unofficial  ones  as  are  in  com- 
mon use.  To  know  at  least  some  of  them  is  essential  to  the 
writing  of  prescriptions,  for  not  only  are  the  official  preparations 
the  ones  that  are  made  of  uniform  strength  throughout  the  United 
States,  but  they  are  the  forms  in  which  a  remedy  can  be  con- 
veniently obtained. 

The  average  dose  is  given  in  the  Pharmacopoeia,  and  this, 
in  most  instances,  is  the  dose  to  learn;  and  since  what  is  desired 
for  the  patient  is  a  therapeutic  dose  of  the  drug  itself,  the  dose  of 
the  preparation  should  be  such  an  amount  as  will  represent  the 
desired  dose  of  the  drug.    The  learning  of  doses  is  greatly  facili- 
tated by  the  pharmacopeial  custom  of  having  one  strength  for 
all  the  more  powerful  preparations  of  a  given  class.    For  example, 
all  fluidextracts  are  of  100  per  cent,  strength;  therefore  their 
dose  is  that  of  the  drug,  but  in  liquid  measure,  i.  e.,  each  cubic 
centimeter  is  equivalent  to  one  gram  of  the  drug.     All  potent 
tinctures  are  of  10  per  cent,  strength,  so  their  dose  is  10  times 
that  of  the  fluidextract.    Most  extracts  approximate  5  times  the 
strength  of  the  drug,  hence  have  a  dose  of  one-fifth  as  much. 
For  preparations,  therefore,  the  doses  do  not  have  to  be  carried 
in  mind  as  separate  things,  but  can  be  instantly  calculated  from 
the  percentage  strength  if  the  dose  of  the  drug  itself  is  known. 
On  account  of  pharmacopeial  uniformity,  the  percentage  strength 
is  easily  learned,  as  shown  above.    As  an  example,  take  the  prep- 
arations of  digitalis;  if  the  dose  of  digitalis  is  taken  as  i  grain 
(0.06  gm.),  that  of  the  fluidextract  is  i  minim  (0.06  c.c.),  that  of 
the  10  per  cent,  tincture  is  10  minims  (0.6  c.c.),  and  that  of  the 
1.5  per  cent,  infusion  is  67  minims,  or  approximately  i  dram 
(4   c.c.).     These  amounts   of   the   specified   preparations  each 
represent  the  dose  of  i  grain  of  digitalis. 

5.  Pharmacologic  Action. — How  the  drug  acts.    This  includes 
the  expected  or  usual  action  and  any  unusual  actions,  from  both 
therapeutic  and  toxic  amounts. 

6.  Toxicology. — The   symptoms   and    treatment   in    case   of 
poisoning. 

7.  Therapeutics. — An  extensive  subject  of  immediate  practical 
importance  to  every  physician,  to  be  studied  in  a  general  way 
with  pharmacology,  but  to  be  studied  in  greater  detail  in  con- 
nection with  the  individual  diseases.     It  is  in  therapeutics  that 
there  is  so  much  of  the  traditional,  the  old-fashioned,  the  empiric; 
and  the  crying  need  of  the  medical  profession  is  that  drug  thera- 
peutics shall  be  based  directly  upon  thorough  pharmacologic 
knowledge  tried  out  by  clinical  tests. 

S.  Administration. — How  best  to  prescribe  or  administer  the 
remedy. 


THE   PHARMACOLOGIC   ACTION  63 

Q.  Cautions  and  Contraindications. — Conditions  in  which  the 
drug  is  dangerous,  or  may  be  prescribed  only  with  special  caution. 

Indication  is  a  term  used  in  medicine  for  the  kind  of  treatment 
"indicated"  or  "pointed  out"  by  the  symptoms  or  disease  of  the 
patient.  We  say,  for  example,  that  "the  indications  in  such  a 
sickness  are  that  the  patient  shall  remain  in  bed,  on  a  milk  diet, 
and  shall  have  a  dose  of  calomel."  Or,  to  put  it  in  another  way, 
we  say  that  "rest  in  bed,  a  milk  diet,  and  calomel  are  indicated," 
i.  e.,  "pointed  to"  by  the  symptoms  as  the  means  of  treatment  to 
be  employed.  Contraindication  has  the  opposite  meaning;  it 
is  a  condition  in  which  the  drug  should  not  be  employed. 


THE   PHARMACOLOGIC  ACTION 

In  this  extensive  field  almost  any  kind  of  "aide-memoire" 
will  be  of  value.  It  will,  therefore,  be  our  general  plan  to  take 
up  in  natural  succession  the  actions  of  each  drug  as  follows: 
first,  its  action  independently  of  the  body,  then  its  local  action, 
its  absorption  into  the  system,  its  systemic  action,  its  elimination 
from  or  disposal  by  the  body,  and  finally  its  action  (remote 
local)  as  it  is  being  excreted.  Such  a  scheme  in  detail  is  illus- 
trated in  the  following  chart : 

A.  On  microorganisms  and  enzymes — action  away  from  the 
body,  e.  g.,  antiseptic  action. 

B.  Local  action — 

1.  On  skin  and  adjacent  mucous  membranes — nose,  throat, 
eye,  vagina,  rectum,  urethra,  bladder. 

external — conjunctiva  and  cornea. 
Eye^  pupil. 

internaK^accommodation. 
eyeball  tension. 

2.  On  alimentary  tract: 

Mouth — taste,  appetite,  saliva,  astringency. 

on    contents — acids,    enzymes,    food    sub- 
stances. 


Stomach 


on  wall — secretion,  movements,  absorption 


of  food  and  drugs,  pain — emetic,  antem- 

etic. 
Intestines — on  contents,  secretion,  movements,  pain, 

character  of  stools. 
Liver,  pancreas — flow  of  bile,  pancreatic  juice,  etc. 

r-     u       ..•        f  j       fat  what  points  or  not  at  all. 
L.  Adsorption  o   drue{  ,  "„ 

'  }  how  rapidly. 


Heart — auricles  and  ventricles 


64  PHARMACOLOGY   AND   THERAPEUTICS 

D.  Systemic  action: 

1 .  On  the  circulatory  organs: 

Blood — corpuscles,  alkalinity,  coagulability. 

rate — slower,   fas- 
ter, 
fore  e — weaker, 

stronger, 
rhythm  —  regular 

or  irregular. 
Arteries — contracted  or  dilated. 
Arterial  pressure — higher  or  lower. 

Always  learn  through  what  mechanisms,  and  how,  an  effect 
is  brought  about.  It  is  not  enough  to  know  simply  that  the  heart 
is  faster  or  slower,  or  weaker  or  stronger. 

2.  On  the  respiratory  organs: 

Movements   (dePth- 
( rate. 

Bronchi — secretions,  muscle. 

Cough — effect  of  drug  depends  on  whether  cough 
is  due  to  excessive  secretion,  or  lack  of  secre- 
tion, or  sensitiveness  of  throat. 

3.  On  the  nervous  system  and  sense  organs: 

Cerebrum — intellect,  emotions,  sleep,  pain,  motor 
area  (motion,  convulsions,  paralysis). 

Cerebellum — equilibrium . 

Medullary  and  basal  centers — vagus,  vasoconstric- 
tor, respiratory,  heat-regulating,  pupil-dilat- 
ing, secretory,  vomiting. 

c,.  .     ,        ,  (muscle  tone. 

Spinal  cord — reflexes  <  ,     • 

I  convulsions,  paralysis. 

Peripheral — sensory,  motor,  secretory. 
Senses — sight,  hearing,  smell,  taste,  touch. 
E     (external  j     (Scc  Local  Actkm  } 
(internal } 

4.  On  muscle  and  bone. 

5.  On  metabolism  and  temperature. 

6.  On  secreting  glands. 

male. 


7-  On  genital  organs 


female — menstruation,  pregnancy, 


labor,  etc. 

how  changed  in  body, 
elimination  by  what  route 
E.  Elimination  or  disposal  of  drug  \      and  in  what  form. 

rapidly  or  slowly — cumu- 
lative. 


THE    PHARMACOLOGIC   ACTION  65 

F.  Remote  local  action — on  excretory  organs  during  elimina- 

tion— by  kidneys,  bladder,  urethra,  skin,  bowels,  lungs, 
mammary  glands;  or  in  urine,  milk,  sweat,  breath,  etc. 

G.  After-effects. 

H.  Untoward  effects — unexpected  or  unusual. 
I.    Tolerance — habit  formation. 

Such  a  scheme  as  the  above  leads  to  completeness  in  the  con- 
sideration of  a  drug's  action. 


PART  II 
INDIVIDUAL   REMEDIES 

SINCE  any  or  all  actions  of  a  drug,  whether  desirable  or  unde- 
sirable, may  result  from  its  administration,  the  proper  use  of  the 
drug  requires  a  knowledge  of  all  its  actions.  Hence  it  is  necessary 
to  study  each  drug  either  as  an  independent  individual  or  as  a 
member  of  a  limited  group  of  drugs  of  nearly  identical  action. 

PROTECTIVES 

A.     DEMULCENTS  AND   EMOLLIENTS 

These  are  agents  which  are  soothing  and  softening  to  epithelial 
tissues.  Their  action  is  essentially  physical  or  mechanical,  and 
is  purely  local.  Those  for  application  to  the  skin  are  called 
emollients;  those  applied  to  mucous  membranes  are  demulcents. 

The  emollients  include  the  unctuous  materials,  such  as  lard 
(adeps),  wax  (cera),  spermaceti  (cetaceum),  petrolatum,  cold 
cream  (unguentum  aquae  rosae),  ointment  of  zinc  oxide,  etc.; 
also  cocoa-butter,  olive  oil  and  other  bland  oils,  talcum  powder, 
glycerin,  rose-water,  and  various  soothing  lotions.  The  object 
of  their  use  is  to  prevent  drying  of  the  epithelium  or  to  soften  and 
protect  dried  or  irritated  tissues.  They  are  employed,  therefore, 
for  chapped  skin,  chafing,  dermatitis,  burns,  etc.  Poultices  and 
hot  fomentations  are  sometimes  considered  emollient,  but  they 
are  best  classed  with  the  hot-water  bag  under  the  heading  Coun- 
terirritants. 

The  demulcents  are  the  mucilaginous  substances,  such  as 
acacia,  tragacanth,  flaxseed  (linum),  slippery  elm  (ulmus  fulva), 
althaea,  sassafras  pith  (sassafras  medulla)  and  Irish  moss  (chon- 
drus  crispus);  also  licorice  (glycyrrhiza) ,  sweet  almond  (amyg- 
dala dulcis),  starch  (amylum),  milk,  white  of  egg,  and  the  bland 
fixed  oils  (almond,  olive,  linseed,  cottonseed,  etc.).  In  the  form 
of  lozenges,  flaxseed,  slippery  elm  and  licorice  are  employed  in 
sore  throat.  In  liquid  form  a  demulcent  may  be  taken  by  mouth 
for  esophageal  or  stomach  irritation,  as  following  the  ingestion 
of  irritant  poisons,  or  injected  by  rectum  for  proctitis  or  colitis  or 
other  irritative  conditions.  (For  Starch  Water,  see  Starch,  in 
Part  I.) 

67 


68  PHARMACOLOGY  AND   THERAPEUTICS 

B.     MECHANICAL   APPLICATIONS 

These  are  for  local  application,  and  act  as  protectives  in  a 
purely  mechanical  way.  Such  are:  collodion,  adhesive  plaster, 
liquid  glass  (solution  of  sodium  silicate),  plaster-of-Paris  (dried 
calcium  sulphate),  and  the  various  dusting-powders,  such  as 
starch,  lycopodium,  and  talcum,  the  last  being  a  silicate  of  mag- 
nesium. 

SWEETENING   AGENTS 

These  are  glycerin,  cane-sugar,  syrup,  saccharin  and  extract 

of  malt. 

SACCHARIN 

Benzosulphinide  (saccharin,  gluside,  C6H4SO2.CONH)  is  an 
acid  anhydride  soluble  in  290  parts  of  water  and  31  of  alcohol. 
Sodium-benzosulphinide  (sodium-saccharin)  is  soluble  in  1.2  of 
water  and  50  of  alcohol.  The  U.  S.  P.  states  that  an  aqueous 
solution  of  i  in  10,000  has  a  sweetness  comparable  with  a  i  in 
20  solution  of  sugar,  i.  e.,  it  is  500  times  as  sweet.  But  it  has  a 
flavor  which  is  not  so  pleasing  as  that  of  sugar.  It  has  been  much 
employed  in  chewing  gum,  chewing  tobacco,  soda-water  and  can- 
ned foods  as  it  is  slightly  antiseptic  and  is  not  fermentable;  but 
it  is  not  a  food  and  lacks  the  caloric  value  of  the  sugar  for  which 
it  is  substituted. 

Mathews  and  McGuigan  considered  it  deterrent  in  digestion 
by  ptyalin,  pepsin,  and  trypsin,  but  Roger  and  Garnier  found 
that  the  acid  anhydride  activated  pepsin  mildly  in  the  same  way 
as  hydrochloric  acid.  In  amounts  of  not  over  5  grains  (0.3  gm.) 
a  day  for  normal  adults  it  was  pronounced  harmless  by  the  U.  S. 
Referee  Board  of  Chemists,  and  Folin.  a  member  of  the  Referee 
Board,  said  of  their  experiments,  "The  negative  character  of  the 
results  obtained  indicates  that  saccharin  in  moderate  doses  is 
not  injurious  to  the  health  of  normal  sound  adults."  Mercier 
took  75  grains  a  day  (5  gm.)  for  14  days  without  harm.  Further- 
more, the  extensive  use  of  the  drug  by  diabetics  has  not  brought 
out  any  deleterious  effects.  The  lethal  dose  for  a  rabbit  is  in 
excess  of  2-,  drams  (10  gm.)  and  it  is  rapidly  eliminated  by  the 
kidneys  in  unchanged  form.  In  medicine  it  is  employed  as  a 
sweetening  agent  for  the  use  of  diabetics  and  the  obese,  and  in 
infants'  or  children's  food  when  it  is  desired  to  omit  sugar,  as 
in  the  "sugar  susceptibles"  of  Kerley.  One  grain  (0.06  gm.)  of 
sodium-saccharin  is  employed  in  place  of  a  tablespoonful  of  sugar. 

NUTRIENTS 

From  a  pharmacologic  point  of  view,  the  substances  coming 
under  this  head  are  sugar,  gelatin,  cod  liver  oil,  olive  oil,  and 
extract  of  malt. 


NUTRIENTS  69 


SUGAR— GLUCOSE 

Sugar  is  official  in  three  forms,  viz.,  cane-sugar  (saccharum) , 
milk-sugar  (saccharum  lactis)  and  dextrose  or  glucose  (glucosum). 
A  saturated  solution  of  cane-sugar  is  "syrupus." 

Cane-sugar. — Locally,  powdered  cane-sugar  has  been  used 
in  dry  form  as  an  application  to  ulcers  and  infected  wounds.  It 
seems  to  promote  osmosis,  to  dissolve  fibrin  and  to  favor  local 
nutrition,  and  it  does  not  form  crusts.  Zweifel,  Sudeck,  and 
others  have  employed  a  50  per  cent,  solution  in  amounts  of  one 
ounce  (30  c.c.)  in  the  vagina  for  leucorrhea.  As  a  postoperative 
measure  to  lessen  shock,  vomiting,  thirst  and  gas  pains,  and  fur- 
nish food,  Barbee  recommends  a  i|  per  cent,  solution  by  rectum 
by  the  continuous  drip  at  30  to  40  drops  per  minute.  Goulston 
and  others  consider  cane-sugar  a  valuable  cardiac  nutrient  even 
when  taken  by  mouth.  Finding  it  non-irritant  and  readily 
absorbed,  Magnus  and  others  have  employed  a  10  per  cent, 
solution  by  hypodermoclysis  as  a  nutrient,  and  claim  that  it  is 
utilized  as  well  as  glucose. 

Milk-sugar  has  no  uses  except  as  a  diluent  in  pharmacy  and 
as  a  food.  It  is  of  interest  that  in  Coleman's  high  calorie  typhoid 
diet  as  much  as  i^  pounds  (715  gm.)  a  day  has  been  given  by 
mouth  and  completely  utilized. 

Glucose,  dextro-glucose  or  dextrose,  is  the  natural  sugar  of 
the  blood.  A  5.4  per  cent,  solution  is  isotonic  with  the  blood. 
Henriques  and  Anderson  maintained  goats  in  good  nutrition 
for  3  weeks  by  a  continuous  flow  through  a  permanent  canula 
into  the  jugular  vein,  of  a  solution  of  glucose,  sodium  acetate, 
inorganic  salts,  and  meat  digested  to  the  amino-acid  stage.  Leo 
states  that  starving  rabbits  given  15  grains  (i  gm.)  of  glucose 
daily  by  the  subcutaneous  or  intravenous  route  survived  5  days 
longer  than  the  controls.  Woodyat,  Sansum  and  Wilder,  by  a 
most  careful  series  of  experiments,  found  that  glucose  in  10  to  50 
per  cent,  solution  can  be  introduced  directly  into  the  veins  at 
rates  corresponding  closely  to  0.85  gm.  of  glucose  per  kilogram 
of  body  weight  per  hour,  without  producing  glycosuria  or  diuresis. 
This  would  be  63  gm.  per  hour  for  a  man  of  70  kilograms  resting 
quietly  in  bed,  and  at  this  rate  would  furnish  6048  calories  per 
day.  They  call  particular  attention  to  the  fact  that  sugar 
tolerance  must  be  measured  by  the  rate  of  administration,  i.  e., 
the  amount  per  hour.  When  given  more  rapidly  than  at  the 
rate  established  glycosuria  and  diuresis  result.  For  example, 
a  lo-kilogram  dog  given  5.4  gm.  per  hour  passed  the  amazing 
amount  of  2800  c.c.  of  urine  in  8  hours.  They  recommend 
intravenous  glucose  as  among  the  best  of  diuretics,  the  dilute 


70  PHARMACOLOGY   AND   THERAPEUTICS 

solutions  serving  to  flush  the  system,  and  the  concentrated  solu- 
tions to  abstract  water  from  the  tissues.  They  warn  that  if  large 
quantities  of  water  are  given  with  the  glucose,  there  is  a  liability 
to  mechanical  failure  of  the  heart,  while  on  the  other  hand  too 
much  of  a  concentrated  solution  will  over-dehydrate  even  to  the 
extent  of  producing  death. 

Burton-Opitz  showed  that  the  viscosity  of  the  blood  was 
increased  by  concentrated  solutions  and  was  readjusted  by  os- 
motic interchange  between  the  blood  and  tissues,  and  Fischer, 
because  of  its  power  to  dehydrate  colloids,  classes  sugar  with  the 
saline  diuretics. 

The  amount  of  sugar  that  can  be  given  by  mouth  or  rectum 
and  disposed  of  is  much  below  the  amount  that  can  be  given  by 
vein.  It  is  impossible  to  produce  glycosuria  by  the  rectal  in- 
jection of  glucose,  and  Hopkins  found  that  while  glucose  by 
mouth  produced  a  hyperglycemia  in  half  an  hour,  20  gm.  sub- 
cutaneously  took  4!  hours  and  100  gm.  by  rectum  4  hours  to 
increase  the  blood-sugar.  Macleod  has  pointed  out  that  neutral 
glucose  solutions  intravenously  produce  an  acidosis,  there  being 
twice  as  much  lactic  acid  in  the  blood  as  normal  and  an  increase 
in  the  hydrogen  ion  content.  This  would  suggest  the  propriety 
of  giving  alkali  with  the  intravenous  solutions. 

Therapeutics. — i.  As  food  in  rebellious  vomiting  (postopera- 
tive, in  pregnancy  or  gastric  disease,  etc.),  malnutrition,  and  car- 
diac decompensation  glucose  may  be  employed  by  continuous 
intravenous  infusion  in  10  to  50  per  cent,  solution  in  amounts 
representing  50  gm.  per  hour.  For  convenience  a  larger  amount 
(300  c.c.)  may  be  given  slowly  two  or  three  times  a  day,  the 
resulting  glycosuria  causing  a  loss  of  only  a  few  grams  of  glucose 
at  most.  2.  During  or  following  operation  it  may  be  employed  as 
a  prophylactic  against  shock  intravenously  or  in  4  to  6  per  cent, 
solution  by  hypodermoclysis  or  the  continuous  drop  proctoclysis. 
3.  As  a  diuretic,  dilute  solutions  are  used  intravenously  or  by 
proctoclysis  in  anuria  and  uremia,  acidosis,  diabetic  coma 
(Joslin),  and  other  toxemias;  and  concentrated  solutions  in  cardiac 
or  nephritic  edema.  Turretini  reports  the  overcoming  of  anuria 
in  four  cases,  two  of  them  mercurial  poisoning. 

GELATIN 

Gelatin  fgelatinum)  is  obtained  by  acting  with  boiling  water 
upon  certain  animal  tissues,  as  the  skin,  ligaments,  and  bones, 
and  allowing  the  solution  to  dry  in  the  air.  It  may  be  obtained 
in  thin,  transparent  sheets  which  are  permanent  if  dry,  but  when 
moist,  readily  putrefy.  It  is  soluble  in  boiling  water,  and  in  the 


NUTRIENTS  71 

proportion  of  i  part  of  gelatin  to  50  of  water  forms  a  jelly  on 
cooling.  In  cold  water  it  does  not  dissolve,  though  it  absorbs 
water  and  swells.  It  is  precipitated  from  solution  by  tannic 
acid  as  a  tough,  leathery  insoluble  mass,  a  matter  of  importance 
in  the  administration  of  capsules  and  of  gelatin-coated  pills.  Be- 
sides its  uses  in  pharmacy  and  as  a  food,  a  sterilized  i  per  cent, 
solution  in  amounts  up  to  100  c.c.  per  day  has  been  employed  by 
hypodermoclysis  and  intravenously  in  hemorrhage  and  aneurysm 
to  increase  the  coagulability  of  the  blood.  It  is  a  protein  food 
from  which  indol  is  not  formed,  hence  has  been  thought  valuable 
in  intestinal  putrefaction,  but  Mendel  considers  it  an  inferior 
food,  useless  for  growth  and  poor  for  the  maintenance  of  nutrition. 
In  shock,  Hogan  uses  it  intravenously  as  a  colloidal  solution 
that  will  remain  in  the  vascular  system  and  so  maintain  the 
volume  of  the  blood.  Any  but  fresh  gelatin  is  prone  to  contain 
putrefactive  products  or  bacteria.  Glycerinated  gelatin,  a  com- 
pound of  equal  parts  of  gelatin  and  glycerin,  is  a  rubbery  mass, 
used  as  a  basis  for  vaginal  suppositories  and  urethral  bougies. 
It  melts  at  the  temperature  of  the  body. 

COD-LIVER   OIL    (OLEUM    MORRHU^) 

This  is  a  fixed  oil,  obtained  from  the  fresh  livers  of  Gadus 
morrhua,  and  of  other  species  of  Gadus.  It  contains  faint  traces 
of  iodinjs  and  bromine  and  sometimes  of  phosphorus.  It  also 
contains  a  vitamine,  for  when  given  with  polished  rice  it  prevents 
beri-beri  (Funk),  and  when  substituted  in  equal  caloric  value 
for  lard  in  a  standard  diet  for  rats  it  induced  growth  which  had 
failed  from  the  lard  (Osborne  and  Mendel).  According  to  Leathes 
it  is  a  fat  with  a  high  percentage  of  unsaturated  fatty  acids, 
so  that  when  taken  as  food  it  saves  the  liver  its  usual  work 
of  desaturation.  The  cheap  oil  obtained  from  putrefactive  livers 
contains  various  bases,  such  as  choline  and  tyramine.  A  watery 
extract  of  such  has  a  vasoconstrictor  action.  Such  oils  are  no 
longer  used. 

Cod-liver  oil  has  a  fishy  odor  and  a  bland,  fishy  taste,  which 
are,  at  least  in  part,  due  to  the  presence  of  free  fatty  acids.  These 
are  abundant  in  the  cheaper  oils,  and  in  the  good  oils  are  more 
readily  produced  in  hot  weather.  As  the  fishy  taste  makes  cod- 
liver  oil  especially  nauseating  to  many  it  is  customary  to  ad- 
minister th«e  oil  in  admixture  with  the  extract  of  malt,  or  in  the 
form  of  a  sweetened  and  flavored  emulsion.  It  has  been  shown 
experimentally  that  emulsified  oils  are  more  readily  absorbable 
than  the  unemulsified,  especially  by  persons  of  poor  nutrition, 
and  it  is  noted  clinically  that  the  emulsion  is  easier  to  take  and 


72  PHARMACOLOGY   AND   THERAPEUTICS 

is  better  borne  by  the  stomach  than  the  pure  oil.  It  should  be 
given  after  meals  as  an  addition  to  the  regular  food,  or  two  or 
three  hours  after  meals,  to  permit  of  ready  digestion  in  the  duo- 
denum. It  should  not  be  given  just  before  meals. 

Therapeutics. — The  great  value  of  cod-liver  oil  is  as  a  nutrient 
in  states  of  poor  nutrition  and  poor  resistance,  hence  its  use  in 
tuberculosis,  chronic  bronchitis,  and  chronic  susceptibility  to 
colds.  It  is  also  of  use  in  spasmophilia  and  rickets.  In  a  negro 
district  in  New  York,  Hess  showed  that  rickets  could  be  pre- 
vented by  giving  cod-liver  oil  at  an  early  age.  Cod-liver  oil  is 
sometimes  employed  by  inunction  in  cases  of  severe  malnutri- 
tion, but  the  usefulness  of  this  procedure  is  seriously  questioned. 
On  subcutaneous  injection  Mills  and  Congdon  (1911)  found  that 
pure  oils  were  slowly  absorbed  by  starving  animals,  and  more 
rapidly  absorbed  when  made  into  an  emulsion  with  3  to  5  per 
cent,  of  lecithin.  It  is  probable  that  such  an  emulsion  would  be 
partly  absorbed  on  rectal  administration. 

Preparations  and  Doses. — Cod-liver  oil — 2  drams  (8  c.c.). 

Emulsion,  50  per  cent,  of  oil,  made  with  acacia  and  flavored 
with  sugar  and  wintergreen — 4  drams  (15  c.c.). 

EXTRACT   OF   MALT    (EXTRACTUM   MALTI) 

This  is  a  liquid  extract  of  malted  barley.  It  is  of  the  con- 
sistence of  thick  honey,  is  sweet,  and  represents  a  large  per- 
centage of  carbohydrate  nutritive  matter.  It  contains  a  small 
amount  of  the  starch-digesting  ferment,  diastase.  Dose,  \  ounce 
(15  c.c.).  Its  chief  use  is  to  hide  disagreeable  tastes,  as  of  cas- 
cara,  cod-liver  oil,  etc. 

COUNTERIRRITANTS 

These  are  remedies  which,  by  irritation  of  the  skin,  are  in- 
tended to  counter  or  check  deeper-lying  affections.  Counter- 
irritation  is  a  very  old  method  of  treatment,  and  it  still  holds  a 
prominent  place  in  therapeutics.  There  are  several  degrees  of 
skin  irritation  that  may  be  produced,  viz.,  rubefacieni,  or  red- 
dening, vesicant,  or  vesicle-producing,  and  epispastic,  or  blistering. 
Beyond  this  an  irritant  may  produce  death  of  tissue.  There  are 
a  few  drugs,  such  as  mercuric  chloride  and  croton  oil,  which  attack 
the  gland-mouths  and  produce  pustules  (pustulant  effect),  but 
these  are  not  now  employed  as  counterirritants.  In  therapeutics, 
in  almost  all  cases,  it  is  desirable  to  confine  the  irritation  to  the 
rubefacient  degree.  In  this  the  superficial  vessels  dilate,  the 
skin  becomes  red  and  warm,  and  there  may  be  smarting.  If  the 


COUNTERIRRITANTS  73 

application  is  too  strong  or  is  allowed  to  remain  too  long,  little 
vesicles  appear,  and  presently,  coalescing,  form  blisters. 

Blistering  is  very  rarely  employed  as  a  remedial  measure. 
Until  recently  blistering  of  the  gums  by  ammonia  was  a  common 
practice  of  dentists;  and  today  a  fly-blister  over  the  knee-joint 
in  cases  of  large  inflammatory  effusions  is  more  or  less  employed. 
However,  in  almost  all  cases  not  only  is  blistering  not  desirable, 
but  it  is  distinctly  harmful.  For  not  only  is  the  blister  a  painful 
lesion,  requiring  treatment  of  itself,  but  it  effectually  prevents 
further  applications  to  the  skin  at  that  spot.  Hence  the  more 
active  agents,  like  mustard  and  heat,  must  be  carefully  watched, 
especially  when  the  patient  is  suffering  from  severe  pain  or  is 
somnolent  or  comatose:  Unintentional  blistering  frequently  re- 
sults because  of  neglect  to  remove  a  mustard  poultice  before 
going  to  sleep.  In  brunets  an  area  of  blistering  or  even  vesica- 
tion  may  be  followed  by  permanent  pigmentation. 

The  mode  of  action  of  counterirritants  has  been  the  subject 
of  much  speculation,  but  the  recognition  in  recent  years  of  a 
relationship  between  the  viscera  and  certain  areas  of  the  skin  and 
body-wall  through  the  nervous  system  has  thrown  much  light 
upon  the  matter.  Dana  (1887)  called  attention  to  "referred 
pains"  as  being  due  to  the  distribution  of  the  nerves,  and  Head 
(1893)  and  Mackenzie  (1902)  determined  that  tenderness  of  the 
superficial  tissues  might  be  a  manifestation  of  inflammation 
or  injury  of  one  of  the  internal  organs.  Recent  physiologic 
studies  have  shown  that  pain  is  elicited  only  in  structures  supplied 
by  the  cerebrospinal  nervous  system,  and  that  viscera  supplied 
by  sympathetic  nerves  have  no  proper  pain  sense.  The  apparent 
pain  in  inflamed  viscera  is  thus  due  to  a  reflex  effect  through  the 
cerebrospinal  nerves.  Hence  the  tenderness  of  appendicitis  is 
mostly  localized  at  one  point,  though  the  actual  situation  of  the 
appendix  is  very  variable;  the  tenderness  of  cholelithiasis  is 
spread  over  an  area  much  greater  than  that  of  the  gall-bladder; 
and  in  pulmonary  tuberculosis  the  superficial  tissues  are  some- 
times so  tender  as  almost  to  preclude  examination  by  percussion. 
Hertz  (1911)  concluded  that  pain  in  disease  of  the  alimentary 
tract  may  be  situated  in  the  skin,  muscles,  and  connective  tissues. 
Sherrington  (1909)  demonstrated  that  on  cutting  certain  nerves 
passing  to  the  intestines  and  stimulating  the  central  cut  ends, 
the  abdominal  muscles  contract  in  a  definite  manner.  Also, 
it  is  a  well-known  physiologic  fact  that  pain  tends  to  cause 
contraction  of  the  splanchnic  arteries.  Tice  and  Larson  (1917) 
found  that  heat  to  the  abdomen  caused  a  rise  in  arterial  pressure, 
but  cold  produced  no  essential  change. 

These  findings  all  go  to  show  a  very  close  relation,  through 


74 


PHARMACOLOGY   AND   THERAPEUTICS 


the  nervous  system,  between  the  tissues  of  the  body  wall  and 
the  contained  viscera,  and  tend  to  explain  how  irritation  of  a 
superficial  area  may  have  a  decided  effect  upon  a  deep-lying  or 
even  remote  viscus  which  is  in  no  way  in  direct  connection  or 
contact  with  the  irritated  area.  In  this  way  may  be  understood 
the  expulsion  of  flatus  by  the  intestines  as  the  result  of  a  turpen- 
tine stupe  applied  to  the  abdomen,  though  the  intestines  have  no 

direct  anatomic  connection 
with  the  anterior  abdominal 
wall;  or  the  effect  of  a  mus- 
tard foot-bath  in  pelvic  con- 
gestion; or  of  a  mustard  paste 
on  the  chest  in  pleurisy  or 
pneumonia.  Mtiller  demon- 
strated that  the  application 
of  an  ice-bag  or  a  hot-water 
bag  to  the  abdomen  has  little 
if  any  effect  upon  the  tem- 
perature of  the  underlying 
viscera.  But  Leonard  Hill 
states  that  the  intrapleural 
temperature  may  be  decid- 
edly raised  by  a  hot  poultice 
on  the  chest  wall. 

As  working  theories,  Head 
and  Hertz  adopt  the  seg- 
mental  relation,  i.  e.,  that  the 
spinal  cord  and  brain  are  in 
regular  segments,  and  that  a 
lesion  affecting  a  nerve  from 
a  given  segment  affects  all  the 
nerves  whose  centers  are  in 
that  same  segment.  "Head's 
areas,"  mapped  out  on  the 
skin  by  Head  as  being  the 
areas  of  tenderness  in  the  va- 
rious visceral  affections,  have 

not,  however,  been  at  all  constant,  and  Mackenzie  has  pointed  out 
that  in  visceral  lesions  pain  and  tenderness  do  not  appear  in  the 
whole  distribution  of  any  one  segment,  but  in  limited  areas  in 
the  distribution  of  two  or  several  segments.  Therefore,  Macken- 
zie suggests  a  regional  relation  rather  than  a  segmental  one. 
Langstroth  (1915)  finds  that  the  areas  over  which  hyperalgesia 
may  be  found  in  disease  of  each  viscus  are  numerous.  The  good 
action  of  reflexes  from  skin  stimuli  mav  be  the  result  of  a  con- 


Fig,  i. — Areas  in  which  pain  is  some- 
times felt:  (A)  In  cardiac  affections;  (B) 
in  affections  of  the  stomach;  (C)  in  affec- 
tions of  the  liver,  stomach,  or  duodenum; 
(D)  in  affections  of  rectum  or  uterus  (after 
James  Mackenzie,  in  "Symptoms  and 
Their  Interpretation"). 


COUNTERIRRITANTS  75 

ferred  hypersensitiveness  to  stimuli  owing  to  the  visceral  in- 
flammation, to  reflex  changes  in  the  circulation,  or  to  other  so 
far  unknown  effects. 

Rubbing  the  back  will  sometimes  distinctly  affect  the  viscera, 
and  Mackenzie's  picture  herewith  suggests  a  reason  for  the  suc- 
cess, in  some  instances,  of  the  osteopathic  plan  of  manipulating 
the  spine  and  its  neighborhood. 

That  counterirritation  may  act  in  other  ways  is  also  possible, 
for  it  is  well  known  to  every  one  that  pain  in  a  sensitive  place 
results  in  a  diminished  sense  of  pain  in  a  less  sensitive  region. 
It  is  probable,  also,  that  the  psychic  suggestive  effect,  as  of  a 
thermocautery,  may  at  times  be  important,  and  that  in  the  treat- 
ment of  muscular  or  other  tissues  in  direct  contact  with  the  skin 
changes  in  the  local  blood-supply  may  account  for  the  remedial 
effect.  In  this  connection  it  is  of  interest  that  Lazarus-Barlow 
has  shown  that  a  muscle  on  the  same  side  as  a  blister  has  a  higher 
specific  gravity  than  the  corresponding  muscle  on  the  unblistered 
side.  And  Wechsberg  has  demonstrated  that  when  abscesses 
were  experimentally  produced  in  rabbit's  legs,  they  were  less 
extensive  and  healed  more  rapidly  on  the  side  to  which  counter- 
irritants  were  applied.  Oliver  found  that  a  mustard  paste  over 
the  liver  sent  the  blood-pressure  from  105  to  135,  and  Roth,  that 
a  large  hot  application  to  chest  and  abdomen  sent  up  the  pressure 
about  8  mm.  in  each  of  two  cases.  But  Wood  and  Weisman 
(1912)  find  that  irritation  of  the  skin  of  the  hand  by  a  mustard- 
bath  just  short  of  producing  dermatitis  does  not  materially 
increase  the  rate  of  blood-flow  in  the  hand,  the  skin  redness 
being  presumably  not  accompanied  by  a  change  in  the  caliber 
of  the  deep-lying  arterioles. 

We  may  sum  up,  then,  by  repeating  that  the  good  effects  of 
counterirritation  may  be  due  to:  (i)  A  segmental  or  regional 
nervous  relation  between  superficial  tissues  and  the  viscera. 
(2)  The  countering  effect  of  a  superficial  pain  over  a  deep-seated 
one.  (3)  A  direct  circulatory  effect.  (4)  A  psychic  effect. 

Counterirritant  Measures. — The  more  commonly  employed 
counterirritant  measures  are:  heat,  cold,  dry-cupping,  and  drugs. 

Heat  is  applied  as  an  electric  pad,  a  hot-water  bottle,  a  hot 
stone  or  flat-iron  wrapped  in  cloth,  or  a  poultice  when  the  desire 
is  to  apply  something  that  will  keep  hot  a  long  time,  or  for  a  short 
time  by  an  electric  lamp  or  the  high-frequency  current.  For  a  sud- 
den application  of  extreme  heat  the  thermocautery  or  the  stupe 
may  be  employed.  A  stupe  is  a  towel  wrung  out  of  very  hot 
water;  a  turpentine  stupe  is  made  by  sprinkling  15  or  20  minims 
of  oil  of  turpentine  on  the  hot  towel.  In  the  use  of  the  thermo- 
cautery for  counterirritant  effect  the  skin  should  not  be  seared, 


j6  PHARMACOLOGY   AND   THERAPEUTICS 

but  merely  reddened  by  the  rapid  passage  over  it  of  the  red- 
hot  iron  or  platinum  point.  Poultices  may  be  made  of  linseed 
meal,  bread,  flour,  bran,  or  hops  boiled  with  water  and  wrapped 
in  cheese-cloth  or  any  thin  fabric.  The  clay  poultice  (cata- 
plasma  kaolini,  U.  S.  P.,  1900),  a  proprietary  name  for  which  is 
"antiphlogistine,"  has  kaolin  and  glycerin  as  its  basis,  with 
added  small  amounts  of  boric  acid,  oil  of  peppermint,  methyl 
salicylate,  and  thymol.  It  has  practically  no  absorption  power 
for  water,  but  acts  largely  by  its  heat  (Roth);  so  for  use  it  is 
heated  in  its  container  and  smeared  over  the  part  with  a  knife 
or  stick.  Roth  (1905)  showed  that  it  had  less  power  as  a  counter- 
irritant  and  retained  heat  for  a  shorter  time  than  a  flaxseed 
poultice. 

Cold  is  for  the  most  part  secured  by  an  ice-bag  or  ice-water 
coil.  It  has  been  ascertained  that  locally  applied  heat  or  cold 
does  not  affect  the  temperature  of  the  viscera  to  any  extent,  and 
that  their  value  in  internal  inflammations  is  not  antiphlogistic 
but  reflex.  Cold  is  often  applied  directly  to  an  injured  or  in- 
fected area  with  the  idea  of  quieting  the  inflammation  and  of 
checking  the  activity  of  bacteria,  but  it  also  lessens  the  resistance 
of  the  tissues  of  the  patient,  and  by  so  doing  may  do  more  harm 
than  good.  Fauntleroy  (1912)  believes  that  in  some  cases  of 
appendicitis  the  ice-bag  is  responsible  for  poor  walling-off  of  the 
lesion  and  poor  resistance  on  the  part  of  the  patient,  as  shown  by 
the  failure  of  the  leukocytes  to  increase  much  above  the  normal. 

Dry-cupping  is  a  process  of  suction  applied  to  the  skin  by 
means  of  specially  made  cups  or  small  tumblers  in  which  a  vacuum 
is  created.  There  are  several  methods  of  obtaining  the  vaccum, 
such  as  swabbing  out  the  cup  with  a  cotton  probe  clipped  in 
alcohol  and  then  lighting  the  alcohol,  or  igniting  some  cotton 
stuck  in  the  bottom  of  the  cup.  The  cup  must  be  instantly  ap- 
plied; and  in  order  that  it  may  hold  and  perform  its  suction,  its 
application  must  be  in  a  region  where  the  tissues  are  soft  enough 
to  be  drawn  upon.  Care  should  be  taken  not  to  burn  the  patient 
and  not  to  leave  the  cups  on  long  in  one  place.  Dry-cupping  is 
not  now  much  employed  because  of  its  awkwardness,  but  in 
extreme  cases,  as  in  edema  of  the  lungs  or  suppression  of  urine, 
may  be  resorted  to. 

Drugs. — These  are  all,  in  the  nature  of  the  case,  general 
protoplasmic  irritants.  The  rubefacients  are:  camphor,  menthol, 
and  chloral  hydrate,  any  two  of  which  solids,  when  mixed  together, 
become  liquefied;  the  spirit  and  liniment  of  camphor,  alcohol, 
chloroform,  methyl  salicylate  (the  liquid  stearopten  which  com- 
poses over  90  per  cent,  of  oil  of  wintergreen  or  oil  of  birch),  oil  of 
turpentine,  tincture  of  iodine,  ammonia,  capsicum,  and  mustard. 


COUNTERIRRITANTS  77 

The  epispastics  are:  ammonia  water  (used  by  dentists  for  blister- 
ing the  gums)  and  cantharides  cerate. 

Mustard  (sinapis)  is  the  ground  seed  of  black  mustard 
(sinapis  nigra).  Its  use  depends  upon  the  development  of  an 
irritant  volatile  oil  when  the  mustard  flour  is  mixed  with  water. 
(See  Glucosides,  Part  I.)  It  may  be  employed  in  the  form  of  a 
mustard-leaf  (charta  sinapis)  dipped  in  tepid  water,  or  as  a  thin 
mustard  paste  made  by  wetting  a  mixture  of  mustard  and  flour 
with  tepid  water  and  wrapping  in  cheese-cloth.  For  an  adult 
the  paste  may  be  made  of  one  part  of  mustard  to  two  or  three  of 
flour,  according  to  the  sensitiveness  of  the  skin;  for  a  child,  one 
part  to  four  or  five  of  flour.  A  mustard  paste  usually  reddens 
sufficiently  in  ten  to  thirty  minutes,  and  its  effect  must  be 
watched  to  prevent  blistering.  As  soon  as  the  skin  is  thoroughly 
reddened  the  mustard  should  be  removed.  Sometimes  with  the 
idea  of  preventing  blistering,  white  of  egg  is  mixed  with  the  paste, 
or  vaseline  is  smeared  over  the  skin  at  the  site  of  application. 
Whether  or  not  such  measures  are  efficacious  we  are  unable 
to  say.  In  pelvic  congestion  with  suppressed  menstruation  a 
mustard  foot-bath  is  sometimes  employed.  It  is  made  by  adding 
a  tablespoonful  of  mustard  to  four  quarts  of  warm  water.  A 
mustard-bath  for  infants  is  prepared  of  half  this  strength.  In 
all  mustard  preparations  very  hot  water  should  not  be  used,  as 
this  destroys  or  retards  the  activity  of  the  enzyme  which  forms 
the  irritant  volatile  oil.  The  enzyme  is  destroyed  at  60°  C. 
(140°  F.).  It  is  to  be  borne  in  mind  that  the  "hotness"  of  a 
mustard-bath  should  be  entirely  due  to  the  mustard  oil  developed, 
and  not  to  its  temperature  as  recorded  by  the  thermometer. 
Cases  of  poisoning  by  mustard  give  the  symptoms  of  volatile 
oil  poisoning.  (See  Carminatives.) 

Cantharides  (cantharis)  is  the  dried  and  powdered  brilliant 
green  beetle,  Cantharis  vesicatoria,  or  Spanish  fly.  Its  active 
constituent  is  0.6  per  cent,  of  cantharidin,  an  acid  anhydride 
which  forms  soluble  salts  with  alkalies.  The  "fly-blister"  is  a 
piece  of  adhesive  plaster  spread  with  cantharides  cerate.  About 
its  only  employment  is  in  large  inflammatory  collections  of  fluid 
in  the  knee-joint,  as  in  acute  rheumatism.  A  fly-blister  about 
two  inches  in  diameter  is  applied  to  the  skin  for  twenty  minutes, 
then  removed,  and  replaced  by  a  flaxseed  poultice.  A  large 
amount  of  serum  collects  beneath  the  skin  and  is  removed  by 
pricking  the  skin. 

Internally,  the  10  per  cent,  tincture  has  been  employed  as  an 
emmenagogue  in  dose  of  5  minims  (0.3  c.c.).  From  its  use  to 
produce  abortion,  and  its  administration  with  the  fancied  purpose 
of  stimulating  sexual  feeling,  many  poisoning  cases  have  resulted. 


78  PHARMACOLOGY   AND   THERAPEUTICS 

It  is  a  violent  irritant,  the  symptoms  following  large  or  undiluted 
doses  being  local  irritation  in  mouth,  esophagus,  stomach,  and 
intestines,  resulting  in  inflammation,  blistering,  or  ulceration, 
with  vomiting,  diarrhea,  bloody  stools,  and  cramps.  The  kid- 
neys and  bladder  also  show  intense  inflammation,  with  bloody 
urine  or  suppression  of  the  urine.  There  is  sometimes  priapism. 
Pregnant  women  may  abort.  The  patient  may  go  into  profound 
collapse,  resulting  in  death.  The  treatment  is  symptomatic, 
demulcents  being  administered  by  mouth  and  rectum,  and  col- 
lapse treated  as  described  later. 

Therapeutics  of  Counterirritants. — i.  To  relieve  pain — mus- 
cular, neuralgic,  and  joint  pains,  as  well  as  those  associated  with 
visceral  affections  (pleurisy,  cardiac  pain,  biliary  and  intestinal 
colic,  and  dysmenorrhea) . 

2.  To  relieve  congestion  and  inflammation — as  in  the  case  of 
inflamed  lymph-nodes,  pelvic  congestion,  and  pneumonia. 

3.  To  promote  absorption — as  of  serous  effusions  in  the  pleural 
or  peritoneal  cavities  or  joints,  in  hydrocele,  and  in  bruises  or 
hematomata. 

4.  To  overcome  tympanites — as  in  the  use  of  the  stupe  in  ty- 
phoid fever  or  postoperative  intestinal  paralysis. 

5.  To  overcome  collapse — as  in  the  use  of  mustard-bath  or 
alternating  hot  and  cold  plunges  for  infants. 

6.  To  check  nose-bleed — ice  to  the  back  of  the  neck. 

7.  To  relieve  cerebral  congestion — as  the  ice-bag  in  headache, 
delirium,  meningitis,  etc.,  or  the  menthol  pencil  in  headache. 

Cautions. — Debility  and  old  age,  in  which  conditions  irritants 
of  all  kinds  tend  to  be  depressing. 

CAUSTICS    (ESCHAROTICS) 

These  are  substances  which  act  by  causing  the  death  of  tissue- 
They  may  destroy  by  consuming  the  tissue,  as  in  the  case  of  sul- 
phuric acid,  or  by  precipitating  protoplasm,  as  by  phenol,  or 
by  causing  an  inflammation  which  results  in  a  slough,  as  in  the 
case  of  arsenic.  The  caustics  are: 

1.  Acids. — Sulphuric,  nitric,  glacial  acetic,  trichloracetic. 

2.  Alkalies. — The  hydroxides  of  potassium,  sodium,  and  cal- 
cium (lime). 

3.  Metallic  Salts. — Silver  nitrate  (lunar  caustic),  copper  sul- 
phate (bluestone),  zinc  chloride,  burnt  alum,  chromium  trioxide 
(chromic  acid),  arsenic  trioxide  (arsenous  acid). 

4.  Carbon  dioxide,  liquid  or  solid. 

5.  Phenol. 

Sulphuric  acid  chars;  nitric  acid  changes  the  part  to  yellow, 


CAUSTICS  (ESCHAROTICS)  79 

and  all  acids  act  by  abstracting  water  and  neutralizing  the  al- 
kalinity of  the  tissues.  They  are  direct  irritants,  even  when 
diluted.  The  alkalies  abstract  water  and  saponify  the  fatty 
substances  of  protoplasm;  they  are  very  penetrating,  and  make 
ulcers  which  are  slow  to  heal.  Chromium  trioxide  comes  in  the 
form  of  deliquescent,  dark  reddish  crystals,  which  decompose 
or  explode  on  the  addition  of  glycerin,  alcohol,  or  other  organic 
substances.  Among  chromate  workers  perforation  of  the  nasal 
septum  is  the  rule,  and  deep  ulcers  of  the  hands  known  as  "chrome 
holes"  may  make  their  appearance.  They  may  be  avoided  by 
protection  from  the  dust.  There  are  also  a  number  of  caustic 
substances,  such  as  mercuric  bichloride,  which  are  not  used  as 
such  in  therapeutics. 

Toxicology. — When  caustic  acids  or  alkalies  are  swallowed, 
they  burn  and  denude  the  tissues  of  mouth,  esophagus,  and  stom- 
ach, and  produce  shock.  To  neutralize  acids,  mild,  non-car- 
bonated alkalies  may  be  used,  such  as  diluted  lime  or  magnesia; 
the  carbonated  alkalies  set  free  too  much  gas.  To  neutralize 
alkalies,  vinegar  and  lemon-juice  are  good.  For  the  burns,  de- 
mulcents, such  as  olive  oil,  lard,  white  of  egg,  milk,  etc.,  are  indi- 
cated. (For  poisoning  by  metallic  salts  and  phenol,  see  later.) 

Therapeutics. — To  remove  exuberant  granulations,  small 
polypi,  warts,  and  hypertrophied  soft  tissues,  as  in  the  nose. 
Caustics  are  now  very  little  employed  except  for  application  to 
small  and  superficial  areas.  Carbon  dioxide,  in  liquid  form  or  in 
sticks,  has  been  used  to  remove  nevi,  and  in  the  treatment  of 
lupus,  sluggish  ulcers,  epitheliomata,  and  leprosy. 

To  cauterize  is  to  sear  the  tissues.  It  may  be  done  with  the 
thermocautery  or  electric  cautery,  or  by  nitric  acid,  phenol 
(carbolic  acid) ,  or  lunar  caustic.  Phenol  is  adapted  for  infected 
cavities  or  sinuses,  the  area  being  afterward  washed  with  alcohol 
to  check  further  penetration  of  the  phenol.  For  dog-bites, 
Bartholow,  of  the  New  York  Department  of  Health  (1911), 
recommends  the  following  in  the  order  of  their  merit,  viz.:  (i) 
Fuming  nitric  acid;  (2)  silver  nitrate;  (3)  the  actual  cautery. 
The  employment  of  the  thermo-  or  electric  cautery  for  the  removal 
of  tissue  is  quite  different  from  its  counterirritant  use,  in  which 
the  skin  should  not  be  seared. 


SCARLET   RED 

Scarlet  red  is  a  name  given  to  several  different  dye-stuffs,  but 
that  recommended  for  medicinal  use  is  toluol-azotoluol-azobeta- 
naphthol.  It  is  known  as  "Scarlet  R,"  and  is  marketed  in  powder 
form  and  in  8  per  cent,  ointment.  From  the  many  published 


80  PHARMACOLOGY  AND  THERAPEUTICS 

reports  it  would  seem  to  have  a  marked  power  to  stimulate  the 
growth  of  epithelium  over  sluggish  wounds  and  ulcers.  Bullock 
and  Rohdenburg  consider  it  a  chemical  irritant  of  slow  absorb- 
ability and  low  toxicity.  Davis,  of  Johns  Hopkins  (1911,  1912), 
records  very  rapid  covering  of  the  surface  of  sluggish  sores  with 
epithelium  having  the  macroscopic  and  microscopic  appearances 
of  normal  skin.  On  the  injection  into  dogs  and  rabbits  of  a  i 
per  cent,  solution  in  oil  he  found  it  non-irritating  and  non-toxic, 
though  it  was  disseminated  through  the  body  and  stained  the 
fatty  tissues.  In  man  he  gave  it  by  mouth,  amounts  of  32  grams, 
63.3  grams,  and  66.5  grams  in  about  four  weeks  producing  no 
symptoms,  and  being  apparently  unabsorbed,  as  they  did  not 
stain  the  fat  of  the  body.  He  therefore  recommends  its  use  in 
gastric  ulcer. 

Hinman  recommends  a  10  per  cent,  solution  in  oil  for  laryn- 
geal  tuberculosis. 

Gurbski  reported  poisoning  in  a  child,  and  Lyle,  in  a  woman. 
Both  followed  application  to  extensive  burns,  and  the  symptoms 
were  headache,  dizziness  and  faintness,  followed  by  nausea, 
violent  vomiting,  abdominal  cramps,  and  pain  on  urination. 
There  was  some  fever,  and  albuminuria  without  casts. 

Dimazon  ointment  is  a  modification  that  does  not  stain  or 
irritate. 

THIOSINAMINE— FIBROLYSIN 

Thiosinamine,  or  allyl  sulphocarbamide,  is  soluble  in  3  parts 
of  alcohol.  It  is  decomposed  by  water,  though  this  change  is 
retarded  by  glycerin.  Fibrolysin  is  the  trade  name  for  a  sterile 
aqueous  solution  of  a  double  salt  of  thiosinamine  and  sodium 
salicylate.  It  is  marketed  in  ampules  of  2.3  c.c.  of  solution 
representing  3  grains  (0.2  gm.)  of  thiosinamine. 

Thiosinamine,  in  dose  of  1-3  grains  (0.06-0.2  gm.),  is  ad- 
ministered by  rectum  or  vagina  in  suppositories,  or  subcuta- 
neously  in  10  per  cent,  freshly  prepared  glycerin-water  suspension 
or  in  15  per  cent,  alcoholic  solution.  It  is  very  irritant  locally. 

Fibrolysin  is  employed  subcutaneously,  intramuscularly,  or 
intravenously.  The  injections  are  given  at  intervals  of  one  to 
three  days,  in  some  cases  as  many  as  60  injections  being  given. 
It  is  less  irritant  locally  than  thiosinamine.  The  action  of  the 
drug  is  to  soften  scar  tissue,  and  perhaps  to  promote  its  absorp- 
tion. Starkenstein  states  that  it  favors  the  hydrolysis  of  collagen 
into  gelatin.  There  are  many  clinical  reports  of  its  value  in 
hypertrophied  scars  of  the  skin;  in  strictures  of  esophagus, 
rectum,  and  urethra;  in  fibrous  ankylosis;  in  arthritis  defor- 
mans;  in  sciatica;  in  opacities  of  the  cornea,  etc.  F.  Ehrlich 


THE   DIGESTIVE   FERMENTS  8 1 

has  employed  it  with  success  to  loosen  the  adhesions  of  small 
epigastric  and  umbilical  hernias.  Such  a  drug  would  seem  to  be 
a  desideratum  in  therapeutics,  yet  it  has  limitations  in  its  power 
to  affect  scar  tissue,  and  its  failures  are  frequent.  It  is  contra- 
indicated  in  active  inflammatory  conditions,  in  tuberculosis 
where  connective-tissue  formation  is  desired,  and  in  ulceration 
of  the  alimentary  tract.  It  is  said  to  be  useless  in  corneal  opac- 
ities of  long  standing. 

CHRYSAROBIN 

Chrysarobin  is  a  neutral  principle  extracted  from  Goa  powder, 
a  substance  found  deposited  in  clefts  or  cavities  of  the  wood  of 
the  araroba  tree  of  Brazil.  It  is  an  orange-yellow  powder,  taste- 
less and  odorless,  but  irritating  to  mucous  membranes  if  con- 
tinuously applied.  Practically  its  only  use  at  present  is  in 
psoriasis,  the  5  per  cent,  ointment  being  employed.  This  is  not 
used  about  the  face,  as  it  may  cause  irritation  of  eyes,  nose,  and 
mouth.  It  sometimes  causes  an  acute  dermatitis  of  arms  or  legs. 

THE   DIGESTIVE  FERMENTS 

PEPSIN 

Pepsin  (pepsinum)  is  an  enzyme  usually  obtained  from  the 
fresh  mucous  membrane  of  the  hog's  stomach.  It  is  almost 
entirely  soluble  in  50  parts  of  water,  and  more  so  in  water  acidu- 
lated with  hydrochloric  acid.  It  acts  in  a  weakly  acid  medium 
to  change  the  insoluble  proteins  of  the  food  into  soluble  protein. 
It  is  destroyed  by  o.oi  per  cent,  sodium  hydroxide  (Sollmann), 
and  it  is  inhibited  by  strong  acid,  human  pepsin,  for  example 
ceasing  to  act  when  the  hydrochloric  acid  reaches  0.3  per  cent. 
By  the  U.  S.  P.  test  it  must  be  able  to  change  3000  times  its  weight 
of  coagulated  egg-albumin  into  soluble  protein.  In  other  words, 
one  grain  of  pepsin  can  digest  at  least  6\  ounces  of  coagulated 
egg-albumin.  Dr.  Gies  has  told  me  of  a  specimen  in  existence 
2-00  times  as  powerful  as  this.  The  U.  S.  P.  test  calls  for  digestion 
at  125.6°  F.  (52°  C.)  for  two  and  one-half  hours  in  water  contain- 
ing one  part  of  absolute  hydrochloric  acid  in  3000. 

Pepsin  is,  therefore,  a  highly  powerful  substance;  and  it 
would  be  a  very  important  therapeutic  agent  were  it  not  for  the 
fact  that  in  almost  all  classes  of  digestive  disturbances  it  is  a 
superfluous  remedy.  For  by  extensive  tests  with  human  gastric 
contents  it  has  been  found  that,  except  in  the  not  very  numerous 
cases  of  achylia  gastrica  with  atrophy  of  the  gastric  mucous 
membrane,  the  stomach  rarely  fails  to  secrete  its  specific  ferments. 


82  PHARMACOLOGY   AND    THERAPEUTICS 

Hence  its  only  use  as  a  digestive  agent  is  in  atrophic  cases,  and 
in  these  it  is  not  always  efficient.  (See  Pancreatin.)  It  may  be 
given  in  capsules,  5  grains  (0.3  gm.)  at  the  beginning  of  a  meal 
and  5  grains  at  the  end,  with  hydrochloric  acid  in  proper  dilution. 
Pepsin  regularly  contains  some  rennin;  its  solutions,  there- 
fore, will  coagulate  milk. 

PANCREATIN 

Pancreatin  (pancreatinum)  is  usually  obtained  from  the  fresh 
pancreas  of  the  hog  or  ox.  It  contains  the  specific  ferments  of 
the  pancreas,  and  represents  its  external  secretion.  There  is  no 
evidence  that  it  also  represents  the  internal  secretion,  and  it  has 
no  power  to  check  pancreatic  diabetes.  Its  notable  actions  are 
those  of  the  enzymes,  trypsin,  amylopsin,  and  steapsin.  It  acts 
best  in  an  alkaline  medium. 

The  Pharmacopoeia  gives  tests  of  its  protein  and  starch- 
digesting  power.  It  specifies  that  i  grain  of  pancreatin  with 
5  grains  of  sodium  bicarbonate  must  be  able  to  peptonize  com- 
pletely 3  ounces  of  cow's  milk  at  104°  F.  (40°  C.)  in  thirty  min- 
utes; that  is,  it  must  change  the  proteins  so  that  the  milk  will 
not  coagulate  on  the  addition  of  nitric  or  acetic  acid.  It  further 
specifies  that  pancreatin  must  be  able  to  change  25  times  its 
weight  of  starch  into  substances  soluble  in  water,  i.  e.,  into 
dextrin,  maltose,  etc.  Hence  pancreatin  would  be  another 
important  therapeutic  agent,  but  that,  like  pepsin,  it  is  seldom 
needed  in  therapeutics. 

When  the  secretion  of  gastric  juice  fails,  as  in  achylia,  the 
choice  is  left  open  of  administering  pepsin  and  hydrochloric 
acid,  or  pancreatin  and  sodium  bicarbonate,  to  bring  about  di- 
gestion in  the  stomach.  But  as  a  rule  no  digestant  at  all  is 
employed. 

In  the  milder  form  of  chronic  pancreatitis  with  emaciation, 
and  in  the  very  rare  cases  of  "pancreatic  infantilism,"  a  condi- 
tion of  stunted  growth  and  chronic  diarrhea,  excellent  results  are 
recorded  from  the  administration  of  pancreatin.  Byron  Bram- 
well  reported  a  boy  of  nineteen  with  development  arrested  from 
the  age  of  eleven  and  chronic  diarrhea  for  the  last  nine  years. 
He  was  bright  and  intelligent  and  not  a  cretin.  His  urine  was 
free  from  sugar.  Under  the  influence  of  pancreatin  by  mouth 
he  grew  five  inches  in  two  years  and  gained  22  pounds.  Rentoul 
had  a  girl  of  eighteen,  in  a  similar  condition  of  stunted  develop- 
ment, gain  9^  pounds  and  grow  2  inches  in  less  than  five  months, 
at  the  same  time  showing  decided  sexual  development  and  general 
improvement.  Thompson  reports  two  such  cases.  They  are 


PANCREATIN  83 

very  rare.  These  results  may  be  due  not  to  the  digestive  power, 
but  to  an  effect  which  the  pancreatin  may  exert  upon  the  ac- 
tivity of  other  glands,  for  instance,  the  thyroid  or  pituitary. 
Indeed,  because  of  the  discovery  of  a  probable  antagonism  be- 
tween the  internal  secretions  of  pancreas  and  thyroid,  pancreatin 
has  been  employed  in  hyperthyroidism. 

In  chronic  pancreatitis  pancreatin  has  been  of  uncertain 
value,  and  in  checking  a  pancreatic  diabetes  has  proved  a  failure. 
But  in  some  cases  it  has  overcome  the  failure  of  fat  and  protein 
digestion  which  regularly  accompanies  pancreatitis,  and  so  has 
resulted  in  improved  nutrition  and  the  disappearance  of  pan- 
creatitic  emaciation.  In  some  cases  of  fat  indigestion  with 
diarrhea,  not  especially  attributable  to  the  pancreas,  as  in  tu- 
berculosis, pancreatin  has  checked  the  diarrhea  and  promoted 
nutrition. 

The  chief  use  of  pancreatin,  however,  is  not  as  a  remedy  for 
internal  administration,  but  as  an  agent  for  peptonizing  milk 
(and  other  protein  foods)  for  invalids.  A  formula  for  peptonizing 
milk  is: 

Pancreatin gr.  v  (0.3  gm.) 

Sodium  bicarbonate gr  xx  (1.3  gm.) 

Water §iv  (120  c.c.) 

Milk Oj  (480  c.c.) 

This  is  kept  warm  at  a  temperature  never  hotter  than  the 
hand  can  bear  continuously  without  discomfort  (115°  F.). 
At  the  end  of  fifteen  minutes  enough  peptones  are  present  to  give 
the  mixture  a  faintly  bitter  taste.  At  the  end  of  an  hour,  or 
sometimes  in  half  an  hour,  the  milk  is  fully  peptonized,  that  is, 
will  not  coagulate  on  the  addition  of  nitric  or  acetic  acid;  it  is 
changed  in  appearance  and  has  a  decidedly  bitter  taste.  To 
obtain  the  greatest  change  of  proteins  to  ammo-acids  requires 
twenty-four  hours  (Short  and  By  waters).  For  gavage  or  rectal 
feeding  milk  should  be  "fully  peptonized";  for  administration 
by  mouth  it  is  usually  peptonized  only  fifteen  or  twenty  minutes 
because  of  the  taste.  At  the  end  of  the  desired  time  it  should  be 
brought  quickly  to  the  boiling-point  to  destroy  the  enzyme,  and 
should  then  be  kept  on  ice.  The  "cold  method"  of  adding  the 
pancreatin  and  sodium  bicarbonate  and  allowing  the  milk  to 
stand  without  warming  is  uncertain  and  unscientific. 

Pepsin  preparations  are  not  suitable  for  peptonizing,  for  they 
invariably  contain  the  coagulating  enzyme,  rennin,  and  conse- 
quently coagulate  the  milk. 


84  PHARMACOLOGY   AND   THERAPEUTICS 

RENNIN  (Rennet) 

Rennin  is  not  a  digestant,  but  is  the  milk-coagulating  ferment 
of  the  gastric  juice.  It  is  obtained  from  the  mucous  membrane  of 
the  fourth  stomach  of  the  calf.  Under  its  influence  the  case- 
inogen  of  milk  changes  to  paracasein,  and  the  latter  takes  cal- 
cium and  forms  an  insoluble  curd.  The  calcium  is  usually  fur- 
nished by  the  calcium  phosphate  of  the  milk,  but  occasionally 
must  be  supplied  by  the  addition  of  a  small  amount  of  calcium 
chloride  or  lime-water.  The  ordinary  rennin  curd  contains  13 
per  cent,  more  calcium  than  the  curd  of  hydrochloric  acid 
(Harris),  and  is  tougher  and  more  cohesive,  though  less  dense 
and  more  readily  acted  upon  by  pepsin.  If  the  stomach  con- 
tents are  highly  acid  or  more  than  very  slightly  alkaline,  the 
rennet  will  not  act.  Hence  if  sodium  bicarbonate  or  more  than 
a  very  little  lime-water  is  added  to  milk,  no  coagulation  takes 
place  at  all;  and  in  marked  cases  of  hyperacidity  the  curd  formed 
is  the  dense  hydrochloric  acid  curd  and  not  that  of  rennet.  Its 
action  is  retarded  by  agitation  unless  in  the  presence  of  hydro- 
chloric acid  (Bernegau).  It  has  been  found  to  coagulate  from 
5000  to  166,000  times  its  weight  of  milk. 

The  use  of  rennet  in  medical  practice  is  to  prepare  junket 
and  whey.  Junket  is  the  whole  coagulated  milk,  and  is  a  valu- 
able food  for  invalids.  It  is  prepared  by  adding  the  commercial 
liquid  rennet,  or  essence  of  pepsin,  or  junket  tablets  dissolved  in 
water,  to  barely  warm  milk,  and  setting  aside  till  the  clotting 
takes  place.  The  process  is  retarded  if  the  milk  is  hot.  The 
junket  may  be  eaten  plain  or  with  cream  and  sugar;  it  may  be 
flavored  with  sherry,  nutmeg,  etc. 

Whey  is  the  liquid  portion  of  the  milk  after  the  rennet  curd 
is  removed.  It  is  obtained  by  breaking  up  the  junket  and  strain- 
ing through  cheese-cloth  or  linen.  It  contains  some  of  the  rennin 
ferment,  a  small  amount  of  soluble  protein  (lactalbumin) ,  a 
slight  amount  of  fat,  about  4  per  cent,  of  milk-sugar,  and  the 
salts  of  the  milk  with  the  exception  of  the  calcium  phosphate. 
It  is  used  as  a  nearly  protein-free  diluent  of  milk  in  infant 
feeding.  Before  it  is  added  to  milk  it  should  be  brought  to  the 
boiling-point  to  destroy  the  rennin;  otherwise  it  will  coagulate 
the  new  milk. 

Rennet  is  used  very  extensively  in  cheese-making  and  in 
the  preparation  of  junket  for  the  table. 

DIASTASE 

Diastase  is  the  starch-digesting  agent  of  barley  malt,  changing 
hydrolized  or  cooked  starch  to  dextrin  and  maltose.  It  has  also 


DIASTASE  85 

some  power  to  hydrolyze  raw  starch.  The  Pharmacopoeia  re- 
quires that  it  be  able  to  convert  not  less  than  50  times  its  own 
weight  of  potato  starch  into  sugars.  It  acts  in  a  neutral  or 
shghtly  acid  medium,  is  retarded  in  its  activity  by  alkalies  (Chit- 
tenden  and  Ely,  and  Kellerman) ,  and  is  destroyed  by  strong  acids. 
Its  digestive  power  is  seldom  needed  in  therapeutics,  except  pos- 
sibly in  pancreatic  disease,  or  where  for  some  obscure  reason  starch 
digestion  is  definitely  defective. 

The  extract  of  malt  is  prepared  by  extracting  barley  malt 
with  water  and  evaporating  to  a  thick,  honey-like  consistence. 
It  contains  much  maltose  and  other  nutritive  matter  and  a  little 
diastase.  As  its  diastatic  activity  is  not  very  great,  it  is  really 
nothing  but  a  form  of  carbohydrate  food  (see  Nutrients).  Owing 
to  its  sweetness  and  thick  consistence  it  is  a  good  vehicle  for  cod- 
liver  oil,  cascara,  and  other  strong-tasting  drugs. 

There  are  also  marketed  some  "extract  of  malt"  preparations 
which  are  really  malt  liquors  of  the  nature  of  beer.  They  con- 
tain about  2  per  cent,  of  alcohol,  by  volume,  and  much  nutritive 
extractive.  In  some  cases  they  are  made  bitter  with  hops. 
They  have  very  feeble  digestant  power  for  starch. 

Taka-diastase,  a  ferment  with  diastatic  properties,  is  obtained 
from  a  mold,  Aspergillus  oryzce,  which  grows  in  Japan  upon  the 
rice  plant. 

Papain  is  an  enzyme  obtained  from  the  juice  of  the  unripe 
fruit  of  Carica  papaya,  a  South  American  papaw  plant.  It  can 
digest  albumin  in  a  medium  that  is  alkaline,  neutral,  or  acid, 
but  acts  best  in  one  that  is  slightly  acid.  It  has  no  special 
indications. 

Ingluvin  is  the  dried  lining  membrane  of  the  chicken's  crop. 
Its  digestive  power  is  not  very  great.  It  has  been  given  in 
doses  of  5  grains  (0.3  gm.)  after  each  meal  in  the  nausea  and 
vomiting  of  pregnancy,  but  its  use  is  purely  empiric. 

Secretin,  owing  to  its  unstable  nature,  has  not  as  yet  come 
into  general  therapeutic  use.  It  is  quickly  destroyed  by  gastric 
juice  and  by  trypsin  (Carlson). 

Hormonal  is  a  preparation  from  the  spleen  of  the  rabbit. 
It  is  said  to  contain  the  same  peristaltic  hormone  as  the  gastric 
mucous  membrane.  Reports  as  to  its  value  differ  widely,  but 
a  number  of  authorities  have  obtained  good  and  continued  action 
of  the  bowels  in  postoperative  tympanites  and  obstinate  chronic 
constipation.  It  tends  to  cause  headache  and  a  marked  fall 
in  blood-pressure,  and  anaphylaxis  has  occurred.  It  is  given  in 
doses  of  15  to  40  c.c.  intravenously  or  intramuscularly,  the  latter 
being  painful. 


86  PHARMACOLOGY   AND   THERAPEUTICS 

THE   INORGANIC   ACIDS 

The  inorganic  acids  in  common  use  for  their  acidity  are 
hydrochloric,  phosphoric,  and  sulphuric.  Their  dose  is  5  minims 
(0.3  c.c.)  well  diluted.  Each  has  an  official  10  per  cent,  dilu- 
tion; but,  as  shown  by  the  following  table,  the  strong  acids 
are  not  10  times  as  strong  as  the  diluted  acids.  The  relative 
percentage  strengths  are  as  follows: 

Hydrochloric  acid.  .  .  .31.9  per  cent. .  .  .Diluted  hydrochloric  acid.  .  .  .10  per  cent. 

Phosphoric  acid 85.0        "       .  .  .Diluted  phosphoric  acid 10 

Sulphuric  acid 92.5        "       .  .  .Diluted  sulphuric  acid 10 

Nitric  acid  is  official,  but  not  the  diluted  nitric  acid. 

Aromatic  sulphuric  acid  (acidum  sulphuricum  aromaticum) 
is  a  10  per  cent,  solution  (by  volume)  of  sulphuric  acid  in  alcohol 
flavored  with  ginger  and  cinnamon. 

Nitrohydrochloric  acid  (acidum  nitrohydrochloricum)  is  made 
by  acting  on  82  parts  of  hydrochloric  acid  with  18  parts  of  nitric 
acid.  A  violent  reaction  takes  place,  the  acids  being  split  up  to 
form  nitrosyl  chlorides  and  chlorine.  The  reactions  are: 

HNO3  +  3HC1  =  NOC1  +  C12  +  2HoO 
2HNO3  +  6HC1  =  2NOC12  +  C12  +  4H2O 

There  is  a  slight  excess  of  hydrochloric  acid  (Arny),  so  that 
nitrohydrochloric  acid  is  a  liquid  containing  free  hydrochloric 
acid,  free  chlorine,  and  nitrosyl  chlorides,  the  original  acids  having 
lost  their  identity.  It  is  a  corrosive  liquid  with  an  unpleasant 
odor.  Diluted  nitrohydrochloric  acid  is  about  one-fourth  this 
strength.  It  does  not  keep. 

Action. — The  strong  acids  are  caustic,  destroying  the  cells  by 
the  absorption  of  water,  by  the  neutralization  of  alkali,  and  by 
other  destructive  chemic  changes.  Sulphuric  acid  chars  organic 
matter;  nitric  acid  turns  it  yellow.  The  diluted  acids  induce  a 
reflex  flow  of  saliva.  This  is  especially  rich  in  protein,  and 
serves  to  take  up  and  neutralize  the  acid.  In  the  stomach  they 
promote  the  flow  of  gastric  juice,  and  secondarily,  by  their 
influence  in  the  production  of  secretin,  promote  the  flow  of 
pancreatic  juice  and  bile. 

Toxicology. — When  a  strong  acid  is  swallowed,  it  causes  burn- 
ing and  corrosion  of  the  mouth,  throat,  esophagus,  and  stomach. 
The  most  corrosive  acids  are  nitric  and  sulphuric.  From  poison- 
ous amounts,  whether  diluted  or  not,  there  are  the  systemic  symp- 
toms of  acute  acidosis.  /.  c.,  dyspnea,  twitching,  convulsions, 
coma,  collapse,  and  death.  Ewing's  conclusions  from  the  experi- 
mental production  of  acute  acidosis  were:  It  is  possible  to  kill 


THE   INORGANIC   ACIDS  87 

animals  by  injection  of  mineral  acids  or  even  of  organic  acids  in 
large  quantity,  and  such  animals  die  with  marked  reduction  in 
the  acid-neutralizing  properties  of  the  blood,  and  with  diminished 
carbon  dioxid  content  sufficient  to  explain  their  peculiar  dyspnea. 
The  urine  shows  marked  excess  of  ammonia  nitrogen  and  diminu- 
tion of  urea.  The  autopsy  findings  indicate  death  from  asphyxia. 
It  must  be  remembered  that  the  basicity  of  the  blood,  that  is, 
its  acid  neutralizing  power,  depends  not  alone  on  alkalies,  but 
also  largely  upon  protein,  urea,  and  other  nitrogenous  sub- 
stances (Ewing).  Fischer  finds  acids  a  cause  of  urticaria  and 
angioneurotic  edema. 

Treatment. — (a)  Local. — The  local  antidotes  in  the  ali- 
mentary tract  are  mild  alkalies,  such  as  soap,  lime,  and  magnesia. 
The  carbonated  alkalies,  such  as  chalk,  sodium  carbonate,  and 
sodium  bicarbonate,  must  be  used  with  great  caution,  if  at  all, 
for  with  the  acid  they  liberate  CO2  gas,  and  this  may  result  in 
collapse  from  sudden  distention  of  the  stomach  or  rupture  of  the 
corroded  stomach  wall. 

(b)  Systemic. — To  combat  the  acidosis  half  an  ounce  of  sodium 
bicarbonate  dissolved  in  one  to  two  pints  of  hot  water  may  be 
given  slowly  by  rectum;  or  a  3.5  per  cent,  solution  of  sodium 
carbonate  may  be  administered  intravenously  (von  Noorden). 
In  chronic  acidosis  the  administration  of  proteins,  and  especially 
of  amino-acids  to  furnish  NH3,  the  natural  antidote  to  acid 
excess,  has  been  tried,  without  great  success.  The  administra- 
tion of  carbohydrates  has  been  of  more  value. 

Therapeutics. —  Nitric  acid  is  occasionally  used  for  the  de- 
struction of  warts  or  small  nevi.  It  causes  pain,  and  often  leaves 
a  scar.  Its  stains  of  the  skin  are  yellow  and  indelible.  Being 
a  powerful  coagulant  of  albumin,  it  is  not  an  aid  to  digestion. 

Hydrochloric  acid  is  sometimes  employed  when  the  natural 
acid  of  the  gastric  juice  is  deficient  or  absent.  It  is  then  given 
in  amounts  of  5-10  minims  (0.3-0.7  c.c.)  in  a  glass  of  water  to  be 
drunk  during  the  meal.  The  throat  will  not  stand  a  stronger 
solution.  This  may  be  repeated  in  half  or  one  hour.  It  is 
believed  by  some  that  in  these  cases  the  acid  serves  as  an  anti- 
septic to  prevent  the  development  of  gas-forming  organisms 
in  the  stomach  and  the  passage  of  putrefactive  bacteria  into  the 
intestines.  There  is  some  good  evidence  against  this  belief. 
Rehfuss  (1917)  finds  that  these  amounts  have  no  perceptible  effect 
on  the  gastric  chemistry,  though  apparently  useful  in  some 
cases  in  overcoming  the  diarrhea  of  achyiia  gastrica.  A  great  dis- 
advantage from  the  long-continued  administration  of  mineral 
acids  is  the  increased  elimination  of  the  alkaline  bases,  with  the 
development  of  a  comparative  acidosis.  The  diluted  hydrochlo- 


88  PHARMACOLOGY   AND   THERAPEUTICS 

ric  acid,  it  will  be  noted,  is  about  one-third  the  strength  of  the 
undiluted. 

Oxyntin,  a  protein  compound  of  hydrochloric  acid,  and  betaine 
hydrochloride  under  the  name  of  acidol,  have  been  introduced  for 
the  administration  of  hydrochloric  acid  in  solid  form.  Acidol  is 
strongly  acid  to  the  taste.  It  is  claimed  that  10  grains  (0.7  gm.) 
of  oxyntin  represent  5  minims  (0.3  c.c.),  and  10  grains  of  acidol 
represent  7.5  minims  (0.5  c.c.)  of  hydrochloric  acid  (U.  S.  P.). 
In  a  careful  research,  Long  (1915)  found  that  betaine  hydro- 
chloride  became  dissociated,  and  its  action  was  almost  equal  to 
that  of  dilute  hydrochloric  acid  of  the  same  concentration.  On 
the  other  hand,  Long  found  that  mixtures  made  by  combining 
hydrochloric  acid  with  protein,  e.  g.,  oxyntin,  hold  scarcely  enough 
acid  to  digest  themselves. 

Dilute  nitric,  nitrohydrochloric,  and  phosphoric  acids  are 
sometimes  employed  for  the  same  purpose  as  hydrochloric. 
There  is  no  reason  for  preferring  them  to  hydrochloric,  which  is 
the  natural  acid  of  the  gastric  juice;  and,  as  noted  above,  nitro- 
hydrochloric is  an  irritant  chlorine  preparation. 

Sulphuric  acid,  both  internally,  in  dose  of  5  minims  (0.3  c.c.) , 
and  externally,  has  been  employed  for  the  night-sweats  of  tu- 
berculosis. In  the  author's  experience  it  is  of  no  value.  It  was 
formerly  the  custom  to  employ  diluted  sulphuric  acid  or  aromatic 
sulphuric  acid  to  bring  quinine-sulphate  into  solution,  but  since 
it  does  so  by  changing  the  insoluble  sulphate  to  the  soluble  bisul- 
phate,  it  would  be  better  to  use  the  bisulphate  at  the  outset  and 
avoid  employing  an  arbitrary  amount  of  acid. 

THE   ORGANIC   ACIDS 

Citric  acid  (acidum  citricum,  HsCetLX):)  occurs  in  large 
quantities  in  fruits  of  the  citrus  family,  the  lemon,  orange,  lime, 
and  grape-fruit;  and  in  milk  to  the  extent  of  0.1-0.25  per  cent. 

Tartaric  acid  (acidum  tartaricum,  H2C4H4O6)  occurs  in  grapes. 

They  are  both  crystalline  solids,  readily  soluble  in  water.  In 
the  duodenum  they  form  sodium  citrate  and  tartrate.  These 
salts  and  the  acids  are  not  readily  absorbed,  and  have  a  laxative 
effect  in  the  intestine.  The  alkaline  salts  are  changed  to  car- 
bonate in  the  blood,  and  so  serve  as  systemic  alkalinizers. 
Lemonade  and  Imperial  drink  are  refreshing  drinks  in  fever. 
The  latter  is  made  by  dissolving  i^  drams  (6  gm.)  of  potassium 
bitartrate  (cream  of  tartar)  in  2  pints  (i  liter)  of  boiling  water, 
and  adding  ?,  ounce  (15  gm.)  each  of  sugar  and  grated  fresh  lemon- 
peel.  In  the  duodenum  potassium  bitartrate,  which  has  an  acid 
reaction,  forms  Rochelle  salt  (potassium  and  sodium  tartrate). 


THE    ORGANIC  ACIDS  89 

When  a  weak  solution  of  a  soluble  citrate  is  mixed  with  or 
injected  into  the  blood,  it  takes  up  calcium  and  has  a  retarding 
influence  upon  the  clotting  of  the  blood.  Because  of  this  action, 
citric  acid  has  been  recommended  in  the  late  stages  of  typhoid 
fever  to  prevent  thrombosis.  But  Rudolf  and  Cole  (1911)  have 
determined  that  citric  acid  administered  by  mouth  does  not 
essentially  influence  the  time  of  coagulation  of  the  blood  either 
in  typhoid  fever  or  in  other  conditions;  and  Addis  (1909)  has 
shown  that  in  amounts  of  60  to  120  grains  (4-8  gm.)  a  day  the 
drug  does  not  affect  coagulability.  Janney  has  administered  up 
to  i  ounce  (30  gm.)  with  sodium  bicarbonate  without  apparent 
harm. 

Formic  acid  (acidum  formicum,  HCOOH)  has  been  employed 
locally  and  internally  in  rheumatism.  It  is  present  in  the  secre- 
tion of  the  sting  of  the  bee,  and  has  been  employed  by  allowing 
bees  to  sting  the  involved  part. 

Acetic  acid  (acidum  aceticum,  CH3COOH)  is  the  essential 
ingredient  of  vinegar.  The  Pharmacopoeia  recognizes  glacial 
acetic  acid  of  99  per  cent,  strength,  which  is  used  for  the  removal 
of  warts;  acetic  acid,  of  36  per  cent,  strength;  and  diluted  acetic 
acid,  of  6  per  cent,  strength.  The  last  is  of  the  strength  of  good 
vinegar.  A  2  per  cent,  solution  is  also  employed  as  an  intra- 
uterine  hemostatic  in  postpartum  hemorrhage.  Trichlor acetic 
acid,  CC13COOH,  is  strongly  caustic,  and  is  employed  in  the 
removal  of  warts,  small  nevi,  and  hypertrophied  tissue,  such  as 
occurs  in  the  nose.  The  acetates  are  freely  soluble  in  water, 
are  readily  absorbed,  and  by  changing  to  carbonate  act  as  agents 
to  alkalinize  the  blood.  They  are  diuretic,  and  their  intravenous 
administration  is  followed  by  a  fall  in  arterial  pressure,  and  dila- 
tation of  the  kidney  arterioles. 

Lactic  acid  (acidum  lacticum,  C3H6O3),  obtained  by  fermenta- 
tion from  sugar-of-milk,  finds  its  chief  use  in  10  to  50  per  cent, 
solution  in  glycerin  as  an  application  to  tuberculous  ulcers  of  the 
throat. 

Recently,  on  the  theory  that  putrefactive  germs  in  the  in- 
testines are  inhibited  by  lactic  acid  germs  and  their  products, 
the  lactic  acid  drinks  have  come  into  extensive  use  both  by  physi- 
cians and  the  laity.  Such  drinks  are:  zoolak,  fermillac,  kumyss, 
sour  milk,  buttermilk,  etc.  Special  strains  of  lactic-acid  bacteria 
are  also  sold  to  be  used  in  making  sour  milk,  or  to  be  swallowed 
in  the  form  of  capsules,  tablets,  or  liquids.  In  the  opinion  of 
Herter,  Bryce,  Mendel,  the  author,  and  others  this  form  of  medi- 
cation has  no  real  value,  many  researches  indicating  little  if  any 
use  for  the  drinks  except  for  their  nutritive  constituents.  Lactic 
acid  drinks  are  prone  to  induce  attacks  of  gastric  hyperacidity, 


90  PHARMACOLOGY  AND  THERAPEUTICS 

and  to  bring  on  rheumatic  manifestations  in  those  subject  to 
rheumatism.  A  recent  claim  that  they  are  of  value  in  diabetes 
requires  extensive  clinical  testing. 

Oxalic  acid  (H2C2O4)  has  no  use  in  therapeutics,  but  is  of 
interest  because  of  the  frequency  of  its  poisoning.  This  usually 
occurs  from  the  drinking  of  solutions  used  in  the  kitchen  for 
brightening  copper  boilers.  The  crystals  resemble  somewhat 
those  of  Epsom  salts.  There  are — (i)  Severe  irritation  of  the 
gastro-intestinal  tract,  with  vomiting,  diarrhea,  and  cramps,  and 
(2)  nervous  manifestations,  from  twitching  of  the  muscles  to 
complete  tetany  (continuous  cramps  of  voluntary  muscles),  and 
convulsions,  coma,  and  death.  When  death  does  not  ensue, 
there  may  be  a  remote  local  effect  upon  the  kidneys  resulting  in 
nephritis.  The  systemic  symptoms  are  those  of  acidosis,  or  of 
the  removal  from  the  system  of  calcium,  for  which  oxalic  acid 
has  a  great  affinity. 

The  chemic  antidote  for  the  stomach  is  a  calcium  salt,  such  as 
lime  or  the  chloride  or  lactate,  to  form  the  insoluble  and  non- 
corrosive  calcium  oxalate.  Even  wall-plaster  may  serve  if  there 
is  no  lime  at  hand.  For  the  systemic  symptoms  the  need  is  to 
alkalinize  and  to  supply  calcium;  therefore  a  pint  (500  c.c.) 
of  a  solution  of  0.25  per  cent,  of  calcium  chloride  with  i  per  cent, 
of  sodium  bicarbonate  may  be  administered  intravenously. 
Copious  drafts  of  water  should  be  given  by  mouth  to  promote  the 
elimination  of  oxalate  by  the  kidneys. 


FRUIT   ACIDS 

The  acids  in  fruits  are  chiefly  acetic,  malic,  citric,  tartaric, 
oxalic,  and  in  some  instances  salicylic  and  boric.  Malic  acid 
and  malates  occur  in  apples,  pears,  currants,  blackberries,  rasp- 
berries, quince,  pineapple,  cherries,  and  rhubarb.  Citric  acid 
and  citrates  occur  in  large  quantities  in  lemons,  oranges,  grape- 
fruit, and  lime,  and  slightly  in  quince,  gooseberry,  strawberry, 
raspberry,  currant,  and  cranberry.  Tartaric  acid  occurs  in 
grapes.  Bertrand  and  Agulhon  have  found  traces  of  boric  acid 
in  many  fresh  fruits  and  vegetables. 

According  to  Blyth,  the  percentage  of  free  acid  present  in 
the  various  fruits  is  as  follows:  Pear,  0.2;  grape,  0.79;  apple, 
0.84;  plum,  0.85;  cherry,  0.91;  peach,  0.92;  strawberry,  0.93; 
apricot,  1.16;  blackberry,  1.19;  raspberry,  1.38;  gooseberry, 
1.42;  prune,  1.5;  mulberry,  1.86;  currant,  2.15.  Lemon-juice 
contains  about  6  per  cent,  of  citric  acid. 

It  must  be  remembered  that  the  relative  acidity  cannot  be 
determined  by  taste,  as  the  proportions  of  sugar  differ  in  the 


ANTACIDS  91 

different  fruits.  For  example,  while  strawberries,  currants, 
gooseberries,  huckleberries,  apples,  pears,  and  prunes  contain 
between  5  and  8  per  cent,  of  sugar,  raspberries,  blackberries, 
apricots,  plums,  and  peaches  contain  less  than  5  per  cent.; 
cherries  contain  10  per  cent.,  and  grapes,  from  15  to  24  per  cent. 
(Blyth,  Fresenius).  The  amount  of  sugar  also  regularly  in- 
creases with  the  ripeness  of  the  fruit. 


ANTACIDS 

The  therapeutically  employed  antacids  are  certain  salts  of 
the  alkalies,  potassium,  sodium,  lithium,  and  ammonium,  and 
certain  salts  of  the  alkaline  earths,  magnesium  and  calcium.  Of 
the  metals  mentioned,  K,  Na,  and  Li  are  ions  of  ready  absorba- 
bility from  the  alimentary  tract,  while  Mg  and  Ca  are  absorbed 
with  comparative  difficulty.  Hence  after  a  local  action  in  the 
stomach  the  salts  of  the  former  for  the  most  part  manifest  a 
systemic  action,  while  those  of  the  latter  have  a  special  intestinal 
activity,  magnesium  salts  being  laxative  and  those  of  calcium 
constipating. 

The  antacids  are  of  two  types: 
I.  Those  of  alkaline  reaction. 

II.  Those  not  of  alkaline  reaction. 


THE  ANTACIDS  OF  ALKALINE  REACTION 

These  can  neutralize  acids,  and  they  have  both  a  local  and  a 
systemic  effect  as  alkalinizers.  They  are  chiefly  oxides,  hydrox- 
ides, and  carbonates,  and  may  be  differentiated  into  two  groups, 
the  caustic  alkalies  and  the  mild  alkalies. 

(a)  The  caustic  alkalies  are   the  hydroxides  of  potassium 
(KOH)  and  sodium  (NaOH)  and  the  oxide  of  calcium  (CaO, 
lime;  Lat.,  calx}.     They  destroy  tissue  by  abstracting  water, 
by  dissolving  albumin,  and  by  saponifying  fats.     Even  in  dilute 
solution  the  potassium  and  sodium  hydroxides  are  more  pene- 
trating and  more  irritant  than  the  other  alkalies.     The  official 
solutions  of  potassium  hydroxide  and  sodium  hydroxide  are  of 
about  5  per  cent,  strength.     They  are  strongly  caustic. 

(b)  The  milder  alkalies  are  the  carbonates  and  bicarbonates 
of  potassium,  sodium,  and  lithium,  and  the  carbonates  and  hy- 
droxides of  magnesium  and  calcium.     The  salts  of  potassium, 
sodium,  and  lithium  are  preferred  for  simple  alkalinity,  the  mag- 
nesium salts  when  there  is  constipation,  and  the  calcium  salts 
when  there  is  diarrhea. 


POTASSIUM,   SODIUM,  AND   LITHIUM 

The  official  mild  alkaline  salts  of  these  ions  are : 

Potassium  bicarbonate  (KHCO3),  soluble  in  3  parts  of  water. 

Potassium  carbonate  (K2CO3),  "salts  of  tartar,"  soluble  in 
0.91  part  of  water. 

Sodium  bicarbonate  (NaHCO3),  "baking  soda,"  soluble  in  12 
parts  of  water. 

Monohydrated  sodium  carbonate  (Na2CO3-fH2O),  dried  so- 
dium carbonate,  soluble  in  3  parts  of  water.  Washing-soda 
is  crystalline  sodium  carbonate  (Na2CO3+ioH2O).  Both  are 
rather  irritating  to  the  tissues. 

Lithium  carbonate  (Li2CO3),  soluble  in  75  parts  of  water. 

All  these  salts  are  insoluble  in  alcohol.  In  aqueous  solution 
the  bicarbonates  slowly  change  to  carbonate  by  loss  of  carbon 
dioxide.  When  heated,  they  change  more  rapidly,  hence  any 
liquid  containing  sodium  or  any  other  bicarbonate  should  not  be 
boiled. 

Potassium. — Since  potassium  chloride  in  the  blood,  in 
amounts  above  i  :  10,000  slows  and  weakens  the  heart  and 
retards  the  activity  of  other  muscles,  the  potassium  ion  has  been 
considered  a  muscle  depressant.  But  in  our  food  we  ingest  at 
least  \  ounce  (15  gm.)  of  potassium  salts  daily,  and  if  the  diet 
is  a  purely  vegetable  one,  sometimes  as  much  as  3  ounces  (90 
gm.)  daily.  Dixon  says  that  we  do  not  get  their  specific  action 
because  they  are  excreted  so  rapidly  by  the  kidneys,  and  Smilie 
has  shown  that  ordinarily  harmless  doses  of  potassium  chloride 
become  severely  toxic  in  those  with  chronic  nephritis.  It  is 
probable  that,  other  things  being  equal,  the  sodium  salts  should 
be  preferred,  unless  cardiac  depression  is  an  object  of  the  medi- 
cation. 

Lithium. — Since  the  lithium  salts  of  uric  acid  are  more 
soluble  than  the  corresponding  sodium  salts,  lithium  has  been 
favored  as  the  alkali  in  gout  and  the  uric-acid  diathesis.  But 
the  quadriurate,  which  seems  to  be  the  responsible  irritant  in 
attacks  of  gout,  is  not  rendered  soluble  by  any  lithium  salt  except 
in  concentrated  solution;  and  is  not  prevented  by  lithium,  so 
far  as  known,  from  forming  in  gouty  subjects.  Daniels  obtained 
no  effect  from  lithium  citrate  alone  in  a  case  of  gout,  but  got  a 
greater  excretion  of  uric  acid  from  atophan  when  lithium  citrate 
was  given  with  it.  She  attributed  a  mobilizing  effect  on  deposited 
urates  to  the  lithium,  though  it  had  no  power  of  itself  to  increase 
the  elimination.  The  lithia  waters  on  the  market  are  chiefly 
remarkable  for  the  minuteness  of  the  amount  of  lithia  present. 


ANTACIDS  93 

several  gallons,  as  a  rule,  containing  not  more  than  a  single 
therapeutic  dose. 

Cleaveland  (1913)  reports  lithium  poisoning  in  himself  on  two 
occasions.  The  first  time  he  took  120  grains  (8  gm.)  of  lithium 
chloride  in  twenty-eight  hours.  The  symptoms  began  after  the 
first  dose  of  2  grams.  There  were  fulness  in  the  head,  dizziness, 
ringing  in  the  ears,  and  blurring  of  the  vision,  followed  by  tremors 
and  marked  prostration.  The  second  time,  several  months 
later,  he  took  60  grains  (4  gm.)  and  the  symptoms  were  repeated. 
He  felt  as  if  he  had  taken  a  large  dose  of  quinine.  There  were  no 
gastro-intestinal  symptoms.  C.  A.  Good  (1903),  in  experiments 
on  cats  and  dogs,  found  that  60  mg.  per  kilo  daily  invariably 
caused  death  sooner  or  later  from  gastro-enteritis. 

Sodium. — Even  sodium  chloride  is  poisonous  under  certain 
circumstances,  and  Jacques  Loeb  believes  that  the  function  of 
potassium  and  calcium  salts  in  the  blood  and  in  sea-water  is  to  pre- 
vent penetration  of  cells  by  too  much  sodium  chloride.  A  num- 
ber of  cases  of  poisoning  from  concentrated  saline  used  intra- 
venously or  by  rectum  instead  of  normal  saline  have  been  reported, 
the  symptoms  being  nausea,  vomiting,  diarrhea,  maniacal  delir- 
ium or  coma,  fever  up  to  104°  F.,  collapse,  and  death.  In  a  fatal 
case  of  a  woman  given  1920  grains  (64  gm.)  by  hypodermoclysis  in 
mistake  for  normal  saline,  Combs  noted  crenation  of  the  red  cells 
in  the  fresh  blood.  Barlow  reports  that  the  drinking  of  a  pint 
or  more  of  the  saturated  solution  is  a  common  method  of  com- 
mitting suicide  in  Chekiang  Province,  China.  Campbell  cites 
a  case  of  death  in  a  boy  of  five  wrho  was  given  a  pound  instead 
of  a  tablespoonful  of  salt  in  a  quart  of  water  as  an  enema  for 
worms.  Brooks  reports  death  in  an  adult  from  an  enema  of  a 
strong  solution.  The  author  has  received  a  report  of  death  in 
one  infant  from  a  colon  irrigation  of  a  i  :  16  solution,  and  gan- 
grene in  another  from  hypodermoclysis  with  the  same  liquid, 
which  was  labeled  "normal  saline." 

The  relation  of  edema  to  salt  retention  is  a  highly  important 
one.  Bryant  reported  the  case  of  a  physician  who  developed 
serious  edema  of  the  legs  after  eating  very  large  quantities  of  salt 
with  his  meals  for  several  weeks.  Stoppage  of  the  habit  resulted 
in  cure.  Sodium  chloride  should  not  be  administered  as  an  in- 
fusion or  rectal  injection  in  parenchymatous  nephritis,  eclampsia, 
or  any  condition  with  edema. 

On  the  other  hand,  too  prolonged  salt-free  diet  may  result  in 
indigestion,  vomiting,  absence  of  acid  in  the  gastric  juice,  weak- 
ness, nervous  irritability,  and  cachexia.  The  author  has  seen  two 
cases  of  nephritis  with  marked  edema,  in  one  of  which  a  salt- 
free  diet  resulted  in  convulsive  twitching  of  the  muscles  all  over 


94  PHARMACOLOGY   AND   THERAPEUTICS 

the  body  which  were  relieved  by  giving  salt,  and  in  the  other  of 
which  it  was  impossible  to  obtain  diuresis  except  when  salt  was 
given.  It  is  estimated  that  an  adult  requires  from  2  to  3  grams  of 
sodium  chloride  a  day. 

Bonninger  states  that  salt  has  a  marked  inhibitory  action  on 
the  secretion  of  gastric  juice,  and  Hamburger  shows  that  it  in- 
activates pepsin.  Best  finds  2  glasses  of  normal  saline  an  effective 
cathartic,  and  Miiller  an  intravenous  of  5  c.c.  of  10  to  15  per  cent, 
two  or  three  times  a  day  effective  against  hemoptysis. 

A  peculiar  effect  of  hypertonic  sodium  chloride  (1.5  c.c.  of  30 
per  cent,  solution)  intravenously  is  the  protection  of  guinea-pigs 
against  anaphylactic  or  proteotoxic  shock.  It  acts  by  lowering 
the  irritability  of  smooth  muscle  (Dale,  Zinsser,  Lieb).  (See  also 
Saline  Infusion.) 

Sodium  Bicarbonate  (Soclii  Bicarbonas).— For  alkalinity ,. 
the  favored  salt  is  sodium  bicarbonate  (NaHCO3).  This  salt 
is  extensively  employed  both  externally  and  internally.  Five 
grains  (0.3  gm.)  will  neutralize  6.2  minims  (0.4  c.c.)  of  hydro- 
chloric acid  (U.  S.  P.),  about  22  minims  (1.5  c.c.)  of  diluted 
hydrochloric  acid,  and  i^  ounces  (45  c.c.)  of  gastric  juice  of 
0.3  per  cent,  strength.  The  alkalinity  of  its  solution  increases 
on  standing,  owing  to  the  loss  of  carbon  dioxide.  On  boiling  it 
sets  free  carbon  dioxide  with  effervescence  and  loses  37  per  cent. 
of  its  weight.  Externally,  in  solution,  it  is  a  solvent  for  dried 
exudates,  such  as  the  crusts  in  seborrheic  eczema;  and  either  in 
solution  or  paste  is  a  soothing  application  in  erythema,  urticaria, 
itching,  insect-bites,  and  burns.  It  is  not  caustic.  To  mucous 
membranes  its  solutions  are  soothing,  and  they  act  as  solvents  for 
thick  mucus. 

Alimentary  Tract. — Sodium  bicarbonate  neutralizes  acids 
and  dissolves  mucus.  According  to  Pawlow  (1897),  it  tends  to 
inhibit  salivary,  gastric,  and  pancreatic  secretion.  But  in 
Pawlow's  laboratory,  Sa witch  and  Zeliony  (1913)  have  demon- 
strated that  when  it  is  applied  to  the  pyloric  mucosa  it  causes 
acid  gastric  juice  to  be  secreted  by  the  stomach  in  gen- 
eral. 

The  effect  of  an  alkali  in  the  stomach  will  vary  greatly  ac- 
cording to  the  nature  of  the  stomach  contents  at  the  time  of 
its  administration.  In  the  resting  period,  sodium  bicarbonate 
merely  dissolves  mucus  and  is  absorbed  as  bicarbonate  into  the 
blood,  to  increase  its  alkalinity  directly.  In  the  digestive  period 
it  reduces  the  secretion  of  gastric  juice,  neutralizes  a  portion  of 
the  hydrochloric  acid,  liberates  the  carminative  carbon  dioxide 
gas,  and  is  absorbed  as  sodium  chloride.  In  cases  of  fermentation 
or  "sour  stomach"  it  may  neutralize  the  organic  acids,  and  so 


ANTACIDS  95 

result  in  the  opening  of  a  spasmodically  closed  pylorus;  while 
at  the  same  time  its  CO2  acts  to  overcome  flatulency. 

The  time  of  administration  must,  therefore,  be  chosen  with 
a  definite  purpose.  Usually  for  hyperchlorhydria  one  hour  or 
two  hours  after  meals  will  be  the  period  of  harmful  excess  of  acid. 
In  continuous  hyperacidity  and  in  fermentative  conditions  a 
dose  an  hour  before  meals  will  tend  to  prepare  the  stomach  for 
the  next  meal;  or  sometimes  a  dose  will  be  necessary  immediately 
after  eating  because  of  abnormal  acid  or  gas  having  been  present 
at  the  commencement  of  the  meal.  A  dose  at  bedtime  tends  to 
check  the  early  morning  acidity,  or  a  dose  on  arising  cleans  the 
stomach  of  acid  and  mucus  before  breakfast.  In  duodenal 
ulcer  it  may  be  needed  when  the  "empty  pain"  comes  on.  In 
alcoholic  gastritis  it  may  be  used  in  solution  for  lavage  to  remove 
excessive  thick  mucus. 

Seelig,  Tierney,  and  Rodenbaugh  find  that  intravenous  sodium 
bicarbonate  solutions  exert  an  effect  beyond  those  of  other  alkalies 
in  raising  blood-pressure,  and  Howell  states  that  a  less  alkaline 
state  of  the  blood  causes  relaxation  of  the  blood-vessels,  while  an 
increase  in  the  alkalinity  improves  their  tone.  But  rapid  excre- 
tion makes  it  difficult  to  produce  more  than  temporary  changes 
in  the  alkalescence  of  the  blood. 

In  mild  conditions  of  acidosis  the  bicarbonate  may  be  given 
by  mouth  in  quantities  to  keep  the  urine  only  slightly  acid.  In 
diabetes,  though  it  favors  the  excretion  of  the  acetone  bodies,  its 
continued  use  may  interfere  with  the  normal  acid-neutralizing 
functions  of  the  body.  Underbill  found  the  blood-sugar  content 
of  a  normal  rabbit  unaffected  by  intravenous  dilute  alkali,  but 
in  dogs  with  hyperglycemia  Macleod  obtained  a  distinct  lowering 
of  the  sugar,  and  Murlin  and  Sweet  have  come  to  the  conclusion 
that  alkalies  serve  to  promote  glucose  oxidation  and  to  favor  the 
work  of  the  pancreas. 

In  severe  conditions  of  acidosis,  as  in  diabetic  coma,  uremia, 
pneumonia,  or  delayed  chloroform  poisoning,  enormous  doses, 
up  to  k  ounce  (15  gm.),  have  been  given  by  mouth;  and  by  rectum, 
by  the  continuous  drop  method,  as  much  as  2  ounces  (60  gm.) 
per  day  in  3  per  cent,  solution.  In  diabetes  these  amounts,  with 
sodium  bicarbonate  intravenously  in  3.5  to  4  per  cent,  solution, 
give  only  occasional  good  results  (von  Noorden) ;  and  the  reason 
for  this  may  be  that  in  diabetes  there  is  no  change  in  the  alkalinity 
of  the  blood  as  judged  by  the  hydroxyl  ions,  though  in  acidosis 
from  mineral  acids  the  blood  is  acid  (Folin).  But  in  the  acidosis 
of  uremia  the  author  has  successfully  employed  if  ounces  (40 
gm.)  of  sodium  bicarbonate  intravenously  in  both  4  and  10  per 
cent,  solutions,  and  there  are  good  reports  from  its  use  in  the 


96  PHARMACOLOGY  AND  THERAPEUTICS 

acidosis  of  pneumonia.  Generalized  edema,  edema  of  the  lungs, 
and  chills  are  reported  following  its  intravenous  use. 

In  rheumatism  and  sometimes  in  gout  it  is  given  until  the 
urine  is  alkaline.  Von'  Noorden  believes  that  in  gout  alkalies 
are  useless  and  perhaps  harmful.  Fauvel  states  that  as  much 
as  i|  ounces  (6  gm.)  a  day  has  no  effect  on  the  excretion  of 
xanthines  or  uric  acid.  By  increasing  the  salts  of  the  blood  it  is 
diuretic.  In  some  cases  it  is  distinctly  laxative. 

The  other  carbonated  alkalies  have  similar  actions,  but  are 
less  employed.  Folin  suggests  that  a  mixture  of  sodium,  potas- 
sium, calcium,  and  magnesium  salts  would  be  better  than  sodium 
bicarbonate  alone.  "Fischer's  solution"  is  hypertonic,  is  ad- 
ministered intravenously,  and  consists  of  i  per  cent,  of  crystalline 
sodium  carbonate  (containing  10  molecules  of  water)  and  1.4 
per  cent,  of  sodium  chloride.  Following  Fischer's  recent  theory 
of  acid  as  a  cause  of  nephritis,  it  has  been  employed  in  this  dis- 
ease, but  neither  the  theory  nor  the  treatment  seems  satisfactory. 

MAGNESIUM 

The  magnesium  antacids  are  the  oxide,  the  hydroxide,  and 
the  carbonate.  Magnesium  perhydrol  is  the  magnesium  per- 
oxide. The  magnesium  oxide  (magnesii  oxidum)  of  the  Pharma- 
copoeia, or  burnt  magnesia,  is  a  very  light,  odorless  white  powder, 
which,  when  exposed  to  air,  slowly  changes  to  carbonate.  One 
part  of  it,  on  being  mixed  with  15  parts  of  water  and  allowed  to 
stand  half  an  hour,  hydrates  and  forms  a  gelatinous  mass.  The 
heavy  oxide  (magnesii  oxidum  ponderosum)  is  3^  times  as 
heavy  and  does  not  readily  hydrate.  Magnesium  hydroxide 
comes  in  the  form  of  a  thick  white  liquid  or  magma  (magma 
magnesice),  commonly  called  "milk  of  magnesia."  This  is 
formed  by  precipitating  a  solution  of  magnesium  sulphate  with 
sodium  hydroxide,  which  leaves  the  magnesium  hydroxide  sus- 
pended in  the  water  in  a  line  state  of  subdivision.  It  contains 
about  4  grains  (0.25  gm.)  of  magnesium  hydroxide  in  each  dram 
(4  c.c.).  Magnesium  carbonate  (magnesii  carbonas),  (MgCO3)4.- 
MgfOH^  +  sHoO,  is  a  white,  insoluble  powder,  capable  of 
neutralizing  acids  with  the  liberation  of  carbon  dioxide  gas. 

These  magnesium  salts  are  all  very  weak  alkalies  without 
any  caustic  action,  but  they  have  considerable  combining  power 
for  acid.  The  oxide  in  the  hydrated  gelatinous  form  will  neutral- 
ize i.\  times  its  weight  of  hydrochloric  acid  (U.  S.  P.).  Benedict 
states  that  magnesium  forces  calcium  from  the  system  and  hinders 
the  calcium  retention  necessary  for  bone  building.  This  might 
be  a  highly  undesirable  effect  from  the  repeated  administration 


CALCIUM  97 

of  milk  of  magnesia  to  infants.  They  all  act  as  cathartics,  and 
will  be  considered  further  under  that  heading.  (See  Magnesium 
Sulphate  under  Cathartics  and  Anesthetics.) 


CALCIUM 

Preparations. — The  mildly  alkaline  salts  are  the  carbonate 
and  the  hydroxide.  The  carbonate  is  insoluble  in  water.  The 
salts  for  systemic  action  are  the  chloride  and  the  lactate,  both 
soluble  in  water,  the  former  being  deliquescent.  The  carbonate 
(CaCO3)  comes  in  two  forms — "prepared  chalk"  (creta  prasp- 
arata)  and  "precipitated  chalk"  (calcii  carbonas  praecipitatus) . 
The  latter  is  in  the  form  of  a  heavy  fine  powder,  may  be  obtained 
pure,  and  is  much  used  in  tooth-powders.  The  former  is  pre- 
pared from  native  chalk  and  contains  impurities,  but  because  of 
a  cohesive  tendency  has  been  much  used  in  liquids  for  internal 
use.  It  comes  in  heavy,  cone-shaped  lumps,  and  is  often  called 
"drop-chalk,"  from  its  method  of  manufacture.  It  constitutes 
30  per  cent,  of  compound  chalk  powder  (pulvis  cretae  compositus) ; 
and  this  is  kept  on  hand  for  the  fresh  manufacture  of  chalk  mixture 
(mistura  cretae),  dose,  2  drams  (8  c.c.).  Unfortunately  this  mix- 
ture contains  the  fermentable  substances,  sugar  and  acacia, 
and  does  not  keep  well. 

The  hydroxide  is  employed  in  the  form  of  a  saturated  solution, 
known  as  lime-water  (liquor  calcis).  Lime-water  is  a  very  weak 
preparation,  containing  only  0.14  per  cent,  of  calcium  hydroxide, 
i.  e.,  about  n  grains  to  a  pint.  It  is  precipitated  by  heat.  To 
neutralize  i  minim  of  hydrochloric  acid,  \  ounce  (15  c.c.)  is 
required.  On  exposure  to  air  it  takes  up  carbon  dioxide  and 
forms  calcium  carbonate,  which  precipitates.  Hence  lime-water 
tends  to  deteriorate,  and  samples  sometimes  contain  almost  no 
calcium  hydroxide.  Before  making  lime-water  the  slaked  lime 
should  always  be  washed  thoroughly,  to  remove  soluble  impuri- 
ties, as  directed  in  the  Pharmacopoeia. 

The  syrup  of  the  lactophosphate  (syrupus  calcii  lactophos- 
phatis),  dose,  2  drams  (8  c.c.),  is  official. 

Action. — As  shown  by  numerous  experiments  calcium  is 
necessary  not  only  for  the  growth  of  bone,  but  also  for  that  of  the 
soft  tissues.  In  adults  it  is  required  in  amounts  equivalent  to 
about  15  grains  (i  gm.)  of  calcium  oxide  a  day.  The  body 
obtains  its  supply  of  calcium  chiefly  from  drinking-water,  eggs, 
milk  and  green  vegetables,  and  slightly  from  animal  flesh, 
cereals,  and  fruits.  Milk  contains  about  0.17  per  cent.,  i.  e., 
slightly  more  than  lime-water.  There  is  as  much  calcium  in  400 
calories  of  milk  as  in  10,000  calories  of  round  steak  and  white 


98  PHARMACOLOGY   AND   THERAPEUTICS 

bread  (Sherman).  The  absorption  of  calcium  is  not  very  ready, 
though  it  is  favored  by  the  acid  of  the  gastric  juice.  From  60  to 
80  per  cent,  of  the  calcium  taken  by  mouth  passes  out  with  the 
feces  (von  Noorden),  part  of  it  having  been  unabsorbed,  and  part 
of  it  absorbed  and  reexcreted.  After  a  hypodermatic  of  a  cal- 
cium salt  it  quickly  appears  in  the  colon  and  as  much  as  50 
per  cent,  has  been  recovered  in  this  way.  In  the  urine  the  or- 
dinary daily  output  is  from  o.i  to  0.5  gm.  per  day,  and  in  the 
feces  0.4  to  0.8  gm.  When  Soborow  gave  8  to  10  gm.  of  chalk  per 
day,  the  calcium  of  the  urine  rose  to  0.7-0.98  gm.  According  to 
Beneker,  in  sickness  and  all  conditions  of  debility,  and  in  starva- 
tion, much  more  than  usual  of  the  calcium  and  magnesium  phos- 
phates may  appear  in  the  urine,  and  sometimes  enormous  quanti- 
ties (2  to  4  gm.  a  day).  Hoppe-Seyler  says  this  excretion  is 
favored  by  rest  in  bed,  the  bones  slowly  atrophying  and  giving 
off  lime  salts.  The  bones  contain  about  4000  times  as  much  cal- 
cium as  the  blood  and  act  as  a  reserve  to  keep  the  calcium  of  the 
blood  normal.  In  infant  feeding  both  calcium  and  fat  may  be 
lost  by  the  formation  of  insoluble  calcium  soaps  in  the  intestines, 
and  Dubois  and  Stolte  suggest  for  its  prevention  the  giving  of 
sodium  or  potassium  carbonates  or  foods  yielding  excess  of  alkali. 
Acid  conditions  favor  excretion  by  the  kidneys  rather  than  by  the 
colon,  hence  in  acidosis  from  diabetes,  and  when  there  is  much  acid 
in  the  food,  the  urinary  output  of  calcium  rises  to  a  high  figure. 

Loeb  found  that  calcium  salts  can  stop  contact  irritability 
of  muscle  and  the  hypersensitiveness  of  the  nervous  system 
induced  by  various  salts.  They  increase  the  rapidity  of  action 
of  the  coagulating  enzymes,  especially  of  the  blood  and  milk. 
They  antagonize  the  action  of  potassium  salts  on  the  heart. 
Loeb  has  recently  suggested  that  the  calcium  in  the  blood  is  for 
the  protection  of  the  cells  from  acids  and  sodium,  the  potassium 
and  calcium  making  a  relative  impermeability  of  the  external 
portion  of  the  protoplasm  of  the  cells.  Meltzer  states  that  cal- 
cium is  capable  of  correcting  the  disturbances  of  the  inorganic 
equilibrium  whether  these  are  in  the  direction  of  increased  irri- 
tability or  the  opposite.  Loeb  noted  that  the  lack  of  sufficient 
calcium  or  the  injection  into  the  animal  body  of  a  salt  capable  of 
precipitating  calcium — e.  g.,  the  oxalate  or  citrate  of  sodium- 
results  in  muscular  twitching.  MacCallum,  Lambert,  and  Vogel 
perfused  an  isolated  limb  with  normal  blood  dialyzed  to  remove 
calcium,  and  produced  extreme  hyperexcitability.  With  blood 
similarly  dialyzed,  but  writh  the  calcium  retained,  there  was  no 
hyperexcitability. 

Tctany  has  frequently  followed  removal  of  the  parathyroid 
glands,  and  both  in  tetany  and  after  parathyroidectomy  the 


CALCIUM  99 

calcium  content  of  the  brain  and  blood  has  been  found  dimin- 
ished (Quest  and  MacCallum  and  Voegtlin).  It  has  also  been 
shown  by  the  last  two  investigators  that  the  nervous  manifesta- 
tions following  parathyroidectomy  may  be  checked  by  the  ad- 
ministration of  calcium  salts.  They  suggest  that  the  absence  of 
the  parathyroids  causes  an  "impoverishment  of  the  tissues  with 
respect  to  calcium,  and  the  consequent  development  of  a  hyper- 
excitability  of  the  nervous  system,  and  tetany."  Marine  and 
Lenhart  found  that  5  c.c.  of  a  5  per  cent,  solution  of  CaCl2  re- 
sulted in  the  recovery  of  a  dog  from  tetany  which  came  on  after 
a  thyroid  operation. 

It  is  well  known  that  infantile  tetany  usually  appears  in  those 
with  rickets.  Erdheim  (1911)  reports  that  extirpation  of  the 
parathyroid  glands  of  white  rats  resulted  in  the  failure  of  full 
calcification  of  dentine  and  enamel  in  the  growing  teeth;  but 
that  on  transplanting  parathyroid  glands,  the  dentine  and  enamel 
layers  became  fully  calcified.  Erdheim  and  Canal  showed  fur- 
ther that  after  removal  of  the  parathyroids  callus  formation  is 
retarded.  These  facts  and  a  number  of  reported  cases  of  human 
tetany  relieved  by  calcium  lead  one  to  think  that  calcium- 
starvation,  or  disturbance  of  calcium  metabolism  through  failure 
of  the  parathyroids,  is  an  important  cause  of  tetany,  and  suggest 
tl\e  intravenous  use  of  calcium  salts  in  this  disease  (Meltzer). 

Coagulation  of  the  Blood. — It  is  an  old  observation  that 
calcium  salts  added  to  the  blood  outside  of  the  body,  or  intra- 
venously, increase  its  coagulability  and  lessen  its  coagulation 
time.  But  it  is  still  a  question  whether  calcium  salts  admin- 
istered by  mouth  have  such  an  effect.  Wright  and  Paramore 
(1905)  reported  a  distinct  difference  within  an  hour  or  less;  but 
Addis  (1909)  found  that  calcium  salts  administered  by  mouth 
increased  the  ionizable  calcium  of  the  blood,  but  not  sufficiently 
even  from  large  doses,  to  alter  the  coagulability.  Rudolf  and 
Cole  (1911),  after  a  very  careful  series  of  studies,  have  come  to  the 
conclusion  that  "the  free  exhibition  of  calcium  lactate  by  mouth 
has  no  appreciable  effect  upon  the  coagulation  of  the  blood"; 
and  Van  Lier  (1912),  after  taking  the  coagulation  time  in  40  per- 
sons before  and  after  administration  of  calcium  lactate,  has  ar- 
rived at  the  same  conclusion.  Lee  and  Vincent  (1915),  however, 
after  several  days  of  100  grains  (6.6  gm.)  of  calcium  lactate  daily 
noted  an  increased  coagulability,  and  further  that  in  obstructive 
jaundice  the  usual  delayed  coagulability  was  overcome.  Too 
high  a  proportion  of  calcium  delays  coagulation.  The  use  of 
calcium  salts  as  local  hemostatics  is  a  failure. 

In  the  clotting  of  milk  by  rennet,  calcium  is  a  necessity.  (See 
Rennet.)  However,  if  an  alkaline  calcium  salt,  such  as  in  lime- 


100  PHARMACOLOGY  AND  THERAPEUTICS 

water,  is  added  to  milk,  the  alkalinity  will  check  the  rennet 
action  and  the  milk  will  not  coagulate.  It  is  probable  that,  as 
a  rule,  any  ordinary  amount  of  lime-water  is  neutralized  by  the 
acid  of  the  gastric  juice,  with  the  formation  of  calcium  chloride. 

Januschke  (1910)  has  shown  that  pleural  effusions  may  be 
checked  by  subcutaneous  injection  of  calcium  chloride,  and 
Chiari  found  that  transudation  and  edema  were  favored  by  the  re- 
moval of  calcium,  which  normally  serves  to  check  the  permeabil- 
ity of  the  vessels.  These  experimenters  and  Meyer  were  able  to 
check  pleural  effusion  resulting  from  diphtheria  toxin,  and  to 
reduce  the  conjunctival  edema  resulting  from  the  application  of 
irritants.  Other  authors  have  reported  good  results  from  the 
use  of  calcium  salts  in  serum-sickness  from  diphtheria  antitoxin,  in 
angioneurotic  edema,  in  chilblains,  and  in  other  conditions  sug- 
gesting abnormal  permeability  of  the  vessels. 

In  the  intestines  calcium  salts  have  been  found  to  retard  or 
check  peristalsis,  to  lessen  intestinal  secretion,  and  to  prevent  the 
action  of  some  of  the  cathartics. 

In  diabetes  Kahn  and  Kahn  obtained  a  fall  in  the  sugar  of  the 
blood  and  Lirine  by  an  intravenous  of  i  to  3!  ounces  (15-50  c.c.) 
of  a  1.4  per  cent,  solution  of  calcium  chloride. 

Calcium  Poisoning. — Large  doses  of  the  chloride  intravenously 
at  first  increase  the  contractility  of  the  heart,  but  soon  bring  about 
its  stoppage  in  systole,  the  arteries  being  contracted  and  the 
pupils  pin-point.  From  50  c.c.  of  1.4  per  cent,  solution  intra- 
venously, Kahn  and  Kahn  noted  great  weakness,  muscular 
pain,  a  fall  in  systolic  and  diastolic  pressures,  and  in  one  case 
collapse  and  coma.  Towles  gave  5  drams  (20  gm.)  of  the  lactate 
daily  by  mouth  for  1 5  days  without  toxic  effects. 

Therapeutics. — Precipitated  chalk  is  used  largely  for  cleaning 
teeth.  Prepared  chalk  is  used  as  an  antacid  and  in  diarrheal 
conditions.  Lime-water  is  used  as  an  addition  to  milk  to  render 
it  more  palatable  and  more  readily  borne  by  the  stomach,  and  to 
increase  its  calcium  content  for  growing  children.  Lime-water 
has  also  been  added  to  skin  lotions  for  eczema  and  dermatitis. 

Calcium  chloride  and  calcium  lactate  have  been  employed — 
(a)  In  hemorrhagic  conditions,  with  questionable  results,  as 
hemophilia,  the  purpuras,  scurvy,  the  hemorrhages  of  typhoid 
fever  and  tuberculosis,  mehrna  neonatorum,  etc.  They  are  not 
indicated  unless  the  coagulability  of  the  blood  is  distinctly  re- 
duced, (b)  As  preliminary  to  operations  in  obstructive  jaundice. 
(c]  In  tetany  and  the  nervous  manifestations  following  para- 
thyroidectomy  or  oxalic  acid  poisoning,  (d)  In  nervous  diseases 
with  hyperexcitability,  as  epilepsy,  chorea,  spasmophilia,  and  the 
tics,  (e)  In  serum  sickness,  urticaria,  angioneurotic  edema, 


THE   ANTACIDS  NOT  OF  ALKALINE  REACTION  IOI 

chilblains,  pleurisy  with  effusion,  etc.  (/)  In  bronchial  asthma, 
to  lessen  nervous  excitability  and  angioneurotic  swelling  of  the 
bronchi,  (g)  In  hay-fever  to  lessen  the  nerve  irritability  which 
leads  to  sneezing. 

To  gain  any  effect  large  doses  must  be  administered  daily. 
Either  the  lactate  or  chloride  may  be  used  in  dose  of  15  to  60 
grains  (1-4  gm.)  three  times  a  day.  The  bitter  saline  taste  of 
the  chloride  may  be  masked  by  peppermint  or  lemonade.  Hy- 
podermatically,  a  4  per  cent,  solution  may  be  employed.  Intra- 
venously, a  i  to  2  per  cent,  solution  of  the  chloride  may  be  given 
in  amounts  of  100  c.c.,  or  a  0.2  per  cent,  solution  of  the  lactate  in 
normal  saline  in  amounts  up  to  500  c.c.  The  chloride  must  not 
be  confused  with  the  antiseptic,  chlorinated  lime  (chloride  of 
lime) . 

THE  ANTACIDS  NOT  OF  ALKALINE  REACTION 

These  do  not  neutralize  acids,  so  are  not  locally  antacid;  but 
in  the  blood  and  tissues  they  break  down  into  alkaline  car- 
bonates, and  as  the  CO2  is  exhaled  increase  the  alkalescence  of  the 
blood.  They  are,  therefore,  systemic  alkalinizers.  These  com- 
pounds are  the  acetic,  citric,  and  tartaric  salts  of  potassium, 
sodium,  and  lithium. 

The  potassium  and  sodium  acetates,  KC2H3O2,  NaC2H3O2, 
and  the  potassium,  sodium,  and  lithium  citrates,  K3-,Na3-,Li3,- 
C6H507,  are  freely  soluble  in  water.  Potassium  bitartrate,  or 
cream  of  tartar  (KHC4H4O6),  is  of  acid  reaction,  and  soluble  in 
200  parts  of  water.  Potassium  and  sodium  tartrate,  or  Rochelle 
salts  (KNaC4H4O6),  is  very  feebly  alkaline  and  is  soluble  in  1.2 
parts  of  water. 

The  acetates  are  readily  absorbed,  and  are  alkalinizing  and 
diuretic.  Dose,  30  grains  (2  gm.). 

The  citrates  and  tartrates  are  absorbed  with  some  difficulty, 
and,  as  a  consequence,  are  more  or  less  cathartic.  A  portion, 
however,  is  absorbed,  and  this  acts  as  an  alkalinizer  and  diuretic. 
After  very  large  doses  slight  amounts  of  both  salts  have  been  re- 
covered from  the  urine. 

In  the  laboratory  tartrates  are  employed  to  produce  a  tubular 
or  tubulo-glomerular  nephritis,  but  from  doses  taken  by  humans 
such  an  effect  does  not  occur,  and  Post  demonstrates  that  even  in 
nephritis  there  is  no  contraindication  to  their  use. 

The  citrates  (see  Citric  Acid),  through  their  affinity  for  cal- 
cium, will  retard  or  prevent  the  coagulation  of  the  blood  and  the 
rennin  clotting  of  milk.  They  have  been  employed  without  any 
decided  success  in  the  late  weeks  of  typhoid  fever  to  lessen  the 


102  PHARMACOLOGY   AND   THERAPEUTICS 

tendency  to  thrombosis.  Lithium  citrate,  in  the  form  of  effer- 
vescing tablets,  each  containing  5  grains  (0.3  gm.),  has  been  much 
employed  to  make  a  palatable  effervescing  alkalinizing  drink. 
One  tablet  may  be  dissolved  in  a  glass  of  water.  Sodium  citrate 
has  been  used  in  infant  feeding,  one  grain  (0.06  gm.)  to  each  ounce 
(30  c.c.)  of  milk  to  reduce  the  density  of  the  curd,  and  two  grains 
(0.12  gm.)  to  an  ounce  (30  c.c.)  to  prevent  completely  the 
rennin  clotting.  In  blood  transfusion  it  is  added  to  the  blood  in 
amounts  to  make  0.2  per  cent,  which  effectually  prevents  clotting 
for  half  an  hour. 

Potassium  bitartrate  (cream  of  tartar)  is  not  readily  soluble 
in  water.  It  forms  Rochelle  salts  in  the  duodenum,  and  is 
laxative.  It  is  a  constituent  of  Imperial  drink.  (See  Citric  Acid.) 

The  hospital  "A.  B.  C.  mixture"  is  an  aqueous  solution  of 
which  each  teaspoonful  contains  5  grains  (0.3  gm.)  each  of  the 
acetate,  bicarbonate,  and  citrate  of  potassium. 

CARMINATIVES 

A  carminative  is  a  remedy  which  tends  to  overcome  flat- 
ulency, that  is,  distention  of  the  stomach  or  colon  with  gas. 
The  aromatics,  which  depend  for  their  action  upon  a  volatile 
oil  or  resinous  constituent,  form  the  great  bulk  of  the  class;  but 
alcohol,  the  distilled  liquors,  chloroform,  ether,  ammonia,  car- 
bonic acid,  as  in  mineral  waters  and  champagne,  and  many  other 
local  irritants  have  strong  carminative  properties.  We  shall 
take  up  here  the  action  of  the  aromatics. 

Pharmacologic  Action  of  the  Aromatics. — Microorganisms.—- 
They  are  antiseptic,  some  of  them  strongly  so,  as  oil  of  eucalyptus. 
Their  use  as  antiseptics,  however,  is  very  limited,  because  of  their 
slight  solubility  in  water.  In  infected  tooth-cavities  the  dentists 
use  oil  of  cloves  or  its  stearopten,  eugenol,  or  oil  of  cinnamon. 

Skin  and  Mucous  Membranes. — They  are  general  protoplasmic 
irritants,  so  are  irritant  to  both  skin  and  mucous  membranes. 
Applied  to  the  tongue  they  have  a  biting  effect,  and  in  the  eye 
cause  smarting.  Rubbed  into  the  skin  they  are  rubefacient, 
i.  e.,  produce  local  dilatation  of  the  skin  vessels,  with  redness  and 
warmth  of  the  part.  It  is  probable  that  they  also  stimulate  the 
sensory  nerve-endings  and  later  depress  them,  for  there  is  more  or 
less  biting  and  tingling,  followed  in  a  number  of  instances  by 
partial  anesthesia  or  numbness.  Peppermint  and  its  stearopten, 
menthol,  distinctly  depress  the  sensory  nerve-endings,  but  at  the 
same  time  stimulate  the  ends  of  the  temperature  nerves  which 
appreciate  cold  (loteyko,  1903),  hence  they  give  a  combined  feel- 
ing of  numbness  and  coolness. 


CARMINATIVES  103 

Alimentary  Tract. — Many  of  them  are  pleasantly  aromatic, 
and  these  are  used  as  flavors,  especially  in  the  dilute  forms  of  the 
official  waters  and  spirits.  They  tend  to  promote  the  appetite, 
but  in  undiluted  form  are  irritant  enough  to  induce  a  protective 
flow  of  saliva.  In  the  stomach  they  are  local  irritants,  and  if 
given  in  sufficiently  concentrated  form,  dilate  the  vessels  and 
produce  hyperemia,  thus  giving  a  feeling  of  well-being  in  the  stom- 
ach region.  At  the  same  time  they  stimulate  motor  activity  and 
the  expulsion  of  accumulated  gases.  The  less  dilute  they  are,  the 
more  prompt  is  their  action.  It  is  generally  believed  that  there 
is  some  stimulation  of  secretion,  so  that  they  are  contraindicated 
in  hyperacidity;  but  Korczynski  (1901)  found  that  from  pepper 
and  mustard  there  was  not  only  no  increased  acidity  or  quantity 
of  the  gastric  juice,  but  even  a  diminution.  It  may  be  that, 
like  alcohol,  they  increase  the  gastric  secretion  through  an  action 
in  the  mouth.  There  seems  to  be  some  furtherance  of  absorp- 
tion by  the  stomach,  presumably  owing  to  the  active  hyperemia. 
Thus  the  functions  of  motion  and  absorption  are  stimulated, 
but  probably  not  that  of  secretion  unless  they  promote  appetite. 

Hertz  (1910)  has  observed  by  the  axrays  that  very  promptly 
following  the  administration  of  a  strong  carminative  by  mouth 
colon  peristalsis  is  set  up.  This  is  a  reflex  action,  and  it  tends  to 
cause  the  expulsion  of  accumulations  of  intestinal  gas,  and  to 
overcome  colic  or  griping.  There  is  also  a  direct  effect,  Muir- 
head  and  Gerald  finding  marked  stimulation  of  isolated  segments 
when  various  oils  were  applied  in  dilutions  of  i  to  50,000.  These 
drugs  are  regularly  added  to  irritant  cathartics  as  "correctives." 

Absorption  is  rapid  from  stomach  and  duodenum. 

Nervous  System. — From  the  local  irritation  in  the  mouth  or 
stomach  there  is  a  general  reflex  stimulation  of  the  vasoconstric- 
tor, the  accelerator,  and  the  respiratory  centers,  so  that  respira- 
tion is  deepened  and  arterial  pressure  raised,  and  momentary 
feelings  of  faintness  are  overcome.  In  this  way  carminatives 
act  as  restoratives.  There  is  also,  after  absorption,  an  apparent 
cerebral  stimulation  which  may  be  effective  in  overcoming  hys- 
teria and  other  conditions  of  nervous  instability. 

Circulation. — Besides  the  reflex  stimulation,  there  is  flushing 
of  the  skin  from  dilatation  of  the  cutaneous  arterioles. 

Genital  Organs. — In  strong  doses  these  oils  tend  to  be  em- 
menagogue  and  abortifacient,  and  many  of  the  cases  of  poisoning 
by  pennyroyal,  rue,  savine,  and  tansy  have  come  from  attempts 
to  produce  miscarriage.  Frequently  the  victim  has  died  in 
agony  without  the  abortion  occurring,  or  has  developed  a  severe 
colitis.  Whether  the  influence  on  the  genital  organs  could  be  a 
factor  in  overcoming  hysteria  has  not  been  studied. 


104  PHARMACOLOGY   AND   THERAPEUTICS 

Elimination. — Part  is  oxidized  in  the  body,  and  the  remainder 
is  eliminated  in  the  urine  and  the  breath,  mostly  in  more  or  less 
changed  aromatic  forms.  For  example,  the  odor  of  the  breath 
of  the  whisky-drinker  is  not  that  of  either  alcohol,  whisky,  or 
fusel  oil,  but  of  a  derivative  of  the  fusel  oil.  The  urine  from 
turpentine  has  an  odor  of  violets,  and  that  after  peppermint  is 
strongly  aromatic,  but  not  minty.  In  the  elimination  there  is  a 
remote  local  irritant  action  on  the  kidneys  and  bronchi,  with 
diuretic  and  expectorant  effects.  The  urine  may  even  be 
rendered  antiseptic,  but  it  is  a  question  whether  large  enough 
amounts  ever  appear  in  the  bronchial  mucus  to  have  an  antiseptic 
value. 

Toxicology. — Poisoning  results — (a)  from  the  irritant  ones 
in  concentrated  form,  with  local  and  systemic  symptoms,  or  (b) 
from  absorption,  with  systemic  symptoms  only.  From  the  very 
irritant  types  there  may  be  violent  gastritis  and  colitis,  with 
vomiting,  diarrhea,  and  abdominal  cramps,  and  perhaps  vomiting 
of  blood  and  bloody  stools.  From  absorption  there  may  be 
overstimulation  of  the  cerebrum,  with  excitement,  great  restless- 
ness, delirium,  and  perhaps  cerebral  convulsions,  or  there  may  be 
dizziness,  stupor,  and  mental  depression  similar  to  that  from 
alcohol  or  ether.  These  states  may  pass  into  collapse,  coma, 
the  convulsions  of  asphyxia,  and  death.  The  kidneys  may  be  the 
seat  of  an  acute  nephritis.  The  treatment  is  to  empty  the  stom- 
ach and  administer  demulcents,  such  as  white  of  egg,  milk,  olive 
oil,  and  mucilaginous  drinks,  and  to  treat  symptomatically  for 
collapse.  The  inflammatory  lesions  must  be  treated  as  when  they 
arise  from  other  causes.  After  recovery  from  the  acute  symptoms 
there  may  be  a  chronic  nephritis  or  colitis.  Poisoning  has  been 
reported  from  asafetida,  nutmeg,  mustard,  and  a  great  many  of 
the  aromatics.  The  colitis  cases  have  mostly  resulted  from  the 
emmenagogue  oils  taken  for  abortifacient  purposes. 

Therapeutics. — A  number  of  carminative  drugs  have  other 
striking  actions  for  which  they  are  of  importance  in  therapeutics, 
and  these  we  shall  study  in  detail  elsewhere.  The  following  is  an 
arrangement  in  therapeutic  groups: 

1.  As  anticolics   (in  intestinal  and  uterine  cramps).     Espe- 
cially employed  for  infants  are  anise,  peppermint,  and  dill  water, 
and  for  adults  the  distilled  liquors,  essence  of  ginger,  spirit  of 
peppermint,  aromatic  spirit  of  ammonia,  and  Hoffmann's  ano- 
dyne (the  compound  spirit  of  ether). 

2.  As  odors  and  flavors — anise,  bitter  almond,  caraway,  cinna- 
mon, coriander,  fennel,  lavender  flowers,  lemon,  nutmeg,  orange- 
peel,  peppermint,  spearmint,  rose,  and  vanilla.     Of  the  waters, 
the  dose  is  i  dram  (4  c.c.);  of  the  spirits,  5  minims  (0.3  c.c.). 


CARMINATIVES  10$ 

3.  As  correctives  of  irritant  cathartics — the  oils  of  anise,  cara- 
way,  cloves,   coriander,   fennel,  and  peppermint.     Of  the  oil, 
|  minim  (0.015  c.c.),  or  of  the  drug,  i  grain  (0.06  gm.),  to  each 
dose. 

4.  For  tympanites,  as  in  typhoid  fever,  pneumonia,  or  follow- 
ing operations.     By  mouth,  oil  of  turpentine,  10  minims  (0.07 
c.c.)  in  capsule,  or  asafetida,  5  grains  (0.03  gm.)  in  pill  or  tincture. 
By  rectum,  oil  of  turpentine,  \  ounce  (15  c.c.),  or  tincture  of  asa- 
fetida or  spirit  of  peppermint,  i  dram  (4  c.c.),  added  to  a  soap- 
suds enema  or  to  8  ounces  or  more  of  infusion  of  chamomile  (an 
aromatic  bitter). 

5.  As  anthelmintics — oil  of  chenopodium  and  oil  of  thyme  or 
thymol. 

6.  As  stimulants  to  mucous  membranes  of  nose  and  throat — 
eucalyptol,  camphor,  and  menthol,  mixed  together  and  inhaled, 
or  diluted  with  liquid  petrolatum  and  used  as  a  spray. 

7.  As  antiseptics  and  anesthetics — oil  of  cloves  or  oil  of  cinna- 
mon in  decayed  tooth,  a  drop  on  cotton.     Eugenol,  the  stearopten 
of  oil  of  cloves,  is  also  used. 

8.  .4s    counterirritants — camphor,    capsicum,    and    menthol, 
and  the  oils  of  mustard,  rosemary,  and  turpentine. 

g.  As  stimulants  in  chronic  skin  diseases,  such  as  eczema — the 
oils  of  cade  and  tar  in  the  form  of  ointment. 

10.  As  stimulants  to  the  growth  of  hair — the  oil  of  mace. 

11.  As  antirheumatics — methyl  salicylate  and  the  oils  of  birch 
and  wintergreen,  externally  as  a  liniment,  and  internally  in  5- 
minim  (0.3  c.c.)  capsules. 

12.  As    antihysterics — asafetida,    camphor,    musk,    sumbul, 
and  valerian. 

13.  As  anti-asthmatics — powdered  cubebs  smoked  in  cigaret 
form. 

14.  As    bronchial    stimulants    (and    perhaps    antiseptics)— 
creosote,  5  minims  (0.3  c.c.),  oil  of  turpentine,  10  minims  (0.7 
c.c.),  terebene,  10  minims  (0.7  c.c.),  and  syrup  of  tar,  i  dram 
(4  c.c.). 

15.  As  diuretics — oil  and  spirit  of  juniper;  the  fluidextracts 
of  buchu  and  uva-ursi,  i  dram  (4  c.c.). 

1 6.  As  urinary  antiseptics — the  oils  of  copaiba,  cubebs,  and 
sandalwood,  and  balsam  of  copaiba,  5  minims  (0.3  c.c.). 

17.  As  emmenagogues — apiol,  from  oil  of  parsley,  and  the  oils 
of  pennyroyal,  rue,  savine,  and  tansy,  3  minims  (0.2  c.c.). 

18.  In  leprosy — chaulmoogra  oil,  5  minims  (0.3  c.c.),  increased 
gradually  to  30  minims  (2  c.c.)  two  or  three  times  a  day  by  mouth, 
or  15  to  75  minims  subcutaneously  every  few  days.     Rogers  uses 
chaulmoogric  (gynocardic)  acid  in  2  per  cent,  solution  intrave- 


106  PHARMACOLOGY   AND   THERAPEUTICS 

nously,  beginning  with  yV  grain  (0.006  gm.)  and  increasing  to  f 
grain  (0.05  gm.). 

For  simple  carminative  action  the  spices  are  much  used,  and 
usually  in  combinations  of  several  carminatives,  as  in  the  com- 
pound tinctures,  compound  spirits,  and  the  aromatic  fluidextract. 
A  favorite  hospital  dose  for  flatulence  is  compound  spirit  of  ether, 
aromatic  spirit  of  ammonia,  compound  tincture  of  lavender,  and 
spirit  of  chloroform,  of  each,  15  minims  (i  c.c.). 

Preparations. — i.  The  volatile  oils  (the  Latin  name  is  given 
in  the  genitive)  are:  Allspice  (pimentse),  anise  (anisi),  birch 
(betulae),  bitter  almond  (amygdalas  amaras),  cade  (cadini), 
cajuput  (cajuputi),  caraway  (cari),  chenopodium  (chenopodii) 
cinnamon  (cinnamomi  or  cassias),  cloves  (caryophylli) ,  copaiba 
(copaibas),  coriander  (coriandri),  cubeb  (cubebae),  dwarf  pine 
needle  (pini  pumilionis),  erigeron  (erigerontis) ,  eucalyptus 
(eucalypti),  fennel  (fceniculi),  juniper  (juniperi),  lavender 
(lavandulae) ,  lemon  (limonis),  mustard  (sinapis),  nutmeg  (myr- 
isticae),  orange-peel  (aurantii),  pennyroyal  (hedeomae),  pepper- 
mint (menthas  piperitae),  rose  (rosae),  rosemary  (rosmarini), 
sandalwood  (santali),  sassafras  (sassafras),  savin  (sabinae), 
spearmint  (menthae  viridis),  tar  (picis  liquidae  rectificati) ,  thyme 
(thymi),  turpentine  (terebinthinae),  wintergreen  (gaultheriae) . 

2.  Tlie  waters  (aquas)  are:     Anise,  bitter  almond,  camphor, 
cinnamon,    fennel,    orange-flower    (aurantii    florum),    stronger 
orange-flower    (aurantii    florum    fortioris),    peppermint,    rose, 
stronger  rose,  spearmint. 

3.  The  spirits  (spiritus) — the  simple  are:  Bitter  almond  of 
i  per  cent,  strength,  dose,  8  minims  (0.5  c.c.) ;  of  10  per  cent, 
strength,  camphor,  cinnamon,  peppermint,  and  spearmint;  of 
5  per  cent,  strength,  juniper,  lavender,  and  wintergreen.     The 
compounds  are:  Aromatic  ammonia  (ammonia,  lemon,  lavender, 
and  nutmeg) ,  compound  ether  (ethereal  oil  and  ether) ,  compound 
juniper  (jumper,  caraway,  fennel),  and  compound  orange  (orange- 
peel,  lemon,  coriander,  anise).     The  compound  spirit  of  ether 
(Hoffmann's  anodyne)  is  no  longer  official. 

4.  The  elixirs. — These  are  sweetened  and  aromatic,  more  or 
less  alcoholic  liquids.     Aromatic  elixir  (elixir  aromaticum)  con- 
tains the  compound  spirit  of  orange,  and  the  elixir  glycyrrhiza  is 
aromatic  elixir  with  the  addition  of  12  per  cent,  of  fluidextract 
of   licorice.     The   liquors   and   cordials,   as   creme   de   menthe, 
absinthe,  Benedictine,  etc.,  are  elixirs.     (See  Alcohol.) 

5.  Stearoptens  used  by  themselves  are:     Benzaldehyde,  from 
oil  of  bitter  almonds;  cinnaldehyde,  from  oil  of  cinnamon;  euca- 
lyptol,  from  oil  of  eucalyptus;  eugenol,  from  oil  of  cloves;  menthol, 
from  oil  of  peppermint;  methyl  salicylate,  from  oil  of  birch  or 


BITTERS  IO7 

wintergreen,  and  also  manufactured  synthetically;  safrol,  from 
oil  of  sassafras,  and  camphor. 

6.  The  spices. — The  spices  are  not  only  aromatic,  but  more 
or  less  hot  and  biting.     Some  of  them  yield  no  oil  and  depend  for 
their  action  on  resinous  ingredients.    They  are  allspice  (pimentae), 
calamus  (calami),  cinnamon,    cardamom,  cloves    (caryophylli) , 
ginger    (zingiberis) ,    black    pepper    (piperis),    and    red    pepper 
(capsici) . 

7.  The  simple  aromatic  tinctures  are :  Asafetida,  bitter  orange- 
peel  (aurantii  amari),  sweet  orange-peel  (aurantii  dulcis),  capsi- 
cum, cardamom,  cinnamon,  ginger,  lemon-peel  (limonis  corticis), 
musk  (moschi),  valerian,  vanilla. 

8.  The  compound  tinctures  are:    Compound  tincture  of  carda- 
mom  (tinctura   cardamomi  composita),   containing  cardamom, 
cinnamon,  and  caraway. 

Compound  tincture  of  lavender  (tinctura  lavandulae  composita) , 
containing  oil  of  lavender,  oil  of  rosemary,  cinnamon,  cloves,  and 
nutmeg. 

Ammoniated  tincture  of  valerian,  a  tincture  of  valerian  made 
with  aromatic  spirit  of  ammonia  as  the  menstruum. 

9.  The  fluidextr acts  are:    Bitter  orange-peel,  buchu,  cubebs, 
eucalyptus,  ginger  (zingiberis),  sumbul,  uva-ursi,  and  the  aromatic 
fluidextract  (fluidextractum  aromaticum).     The  last  is  a  fluid- 
extract  of  aromatic  powder  (pulvis  aromaticus)  which  contains 
cinnamon  and  ginger,  each,  35  parts,  and  cardamom  and  nut- 
meg, each,  15  parts. 

Doses. — These  vary  somewhat.  Where  the  drugs  have  no 
other  marked  quality,  their  carminative  doses  are:  Powdered 
drug,  15  grains  (i  gm.) ;  oils,  5  minims  (0.3  c.c.);  waters,  i  dram 
(4  c.c.);  spirits,  10-30  minims  (0.7-2  c.c.);  tinctures,  30  minims 
(2  c.c.);  aromatic  fluidextract,  30  minims  (2  c.c.). 

BITTERS 

These  are  substances  that  are  employed  to  give  a  bitter  taste, 
the  object  of  their  administration  being  to  improve  the  appetite. 
When  the  appetite  is  below  normal,  a  strong  stimulation  of  the 
taste-buds  will  often  restore  it;  and  substances  with  a  bitter 
taste  that  is  not  otherwise  disagreeable  tend  to  act  as  stimulants 
to  the  taste-buds. 

That  appetite  is  important  for  digestion  has  been  demon- 
strated by  Pawlow  and  his  followers.  They  discovered  "that  the 
stomach  of  a  hungry  dog  would  secrete  gastric  juice  if  he  saw  or 
smelled  food,  even  though  there  was  no  food  in  the  stomach. 
This  is  known  as  the  "appetite"  or  "psychic"  gastric  juice. 


108  PHARMACOLOGY   AND    THERAPEUTICS 

They  also  found  that  some  foods  would  not  digest  at  all, — for 
example,  white  of  egg, — if  they  were  put  in  the  empty  stomach 
without  arousing  the  appetite,  as  through  a  fistula  while  the 
animal  slept.  That  is,  they  were  incapable,  by  direct  action  on 
the  stomach  wall,  of  inducing  the  stomach  to  secrete.  But 
Pawlow  noted  further  that,  on  showing  the  dog  food,  the  appetite 
juice  would  form  and  would  act  on  the  egg-albumin;  and  that 
the  products  of  this  primary  digestion  would  then  stimulate  the 
stomach  wall  and  induce  the  secretion  which  continued  the  diges- 
tion. Hence  the  appetite  juice  is  of  great  importance  in  starting 
digestion ;  and  since  the  formation  of  the  appetite  juice  is  favored 
by  bitters,  these  may  be  considered  aids  to  digestion  in  atonic 
cases. 

Moorhead,  1901,  found  that  in  normal  dogs  bitters  had  no 
effect  or  were  depressing,  while  in  cachectic  dogs  they  distinctly 
stimulated  appetite,  and  the  secretion  of  gastric  juice.  Barisoff 
gave  tincture  of  gentian  to  a  dog  with  the  end  of  the  severed 
esophagus  opening  outside  so  that  substances  swallowed  did  not 
reach  the  stomach.  He  followed  this  with  a  meal,  and  found  the 
average  amount  of  gastric  juice  increased  over  30  per  cent,  by 
the  bitter.  An  excess  of  bitter  checked  the  secretion.  Carlson's 
experiments  with  normal  humans  and  dogs  showed  increased  ap- 
petite, but  an  inhibition  of  the  hunger  contractions.  He  thinks 
that  the  effect  of  a  bitter  is  purely  psychic. 

The  bitter  effect  on  appetite  is  solely  the  local  one  on  the  taste- 
buds,  so  it  is  not  obtained  if  the  bitter  is  hidden,  as  in  capsules 
or  gelatin-coated  pills,  or  if  it  is  disguised  by  sweetening  agents 
or  flavors.  It  requires  for  its  development  that  the  bitter  shall 
be  taken  just  preceding  the  usual  time  for  eating;  that  is,  from 
ten  to  twenty  minutes  before.  If  the  appetite  is  already  normal, 
the  bitter  may  not  increase  it,  and  may  even  lessen  it.  If  the 
stomach  and  bowels  are  deranged,  a  bitter  may  nauseate. 

The  bitters  are  classed  as  the  simple  bitters,  which  have  no 
effect  on  taste  other  than  bitterness,  and  the  aromatic  bitters, 
which,  in  addition  to  the  bitter  principle,  contain  a  volatile  oil 
or  resinous  aromatic. 

The  simple  bitters  are:  barberry  (berberis),  calumba,  con- 
durango,  dandelion  (taraxacum),  gentian,  and  quassia.  These 
may  be  used  in  the  form  of  an  infusion,  dose,  7}  ounce  (15  c.c.), 
or  tincture,  dose,  i  dram  (4  c.c.),  diluted  to  give  a  bitter  drink. 
The  powerful  pharmacologic  drugs,  nux  vomica,  with  its  alkaloid r 
strychnine,  and  cinchona,  with  its  alkaloid,  quinine,  are  often 
employed  also  as  simple  bitters.  Quassia-cups  are  used  in  some 
households.  They  are  turned  out  of  quassia  wood  and  impart 
an  intense  bitterness  to  water  allowed  to  stand  in  the  cup  for 


ANTI-BITTERS — CHARCOAL  IOQ 

fifteen  minutes.  The  cups  retain  their  power  for  a  long  time. 
Infusion  of  quassia  is  also  employed  as  a  bitter,  as  an  enema  for 
pin-worms,  and  as  an  insecticide  in  agriculture. 

Orexine  hydrochloride  and  tannate,  bitter,  crystalline  bodies, 
are  also  used  in  dose  of  5  grains  (0.3  gm.).  They  are  soluble  in 
about  15  parts  of  water. 

The  aromatic  bitters  are:  wormwood  or  vermouth  (absinthi- 
um), chamomile  (anthemis),  German  chamomile  (matricaria) , 
bitter  orange-peel,  and  serpentaria. 

There  are  two  aromatic  bitter  tinctures  which  are  favorite 
appetizers,  viz.,  compound  tincture  of  gentian  (tinctura  gentianae 
composita),  made  of  gentian,  cardamom,  and  bitter  orange-peel, 
dose,  i  dram  (4  c.c.),  and  compound  tincture  of  cinchona  (tinctura 
cinchonae  composita),  made  of  red  cinchona,  serpentaria,  and 
bitter  orange-peel,  dose,  i  dram  (4  c.c.). 

ANTI-BITTERS 

There  are  two  vegetable  substances  that  possess  the  peculiar 
property  of  abolishing  the  appreciation  of  bitter  taste.  They  are 
yerba  santa  (eriodictyon) ,  a  leaf,  and  gymnemic  acid,  a  whitish 
powder  which  is  soluble  in  water,  dose,  5  grains  (0.3  gm.). 

The  syrup  of  yerba  santa,  dose,  i  dram  (4  c.c.),  has  been 
much  employed  as  an  addition  to  bitter  medicines,  especially 
quinine.  It  lessens  the  appreciation  of  bitter  taste,  but  in  swal- 
lowing hardly  acts  rapidly  enough  to  check  the  taste  of  a  bitter 
substance  mixed  with  it;  in  fact,  to  get  the  real  anti-bitter  effect, 
it  is  necessary  to  hold  the  yerba  santa  preparation  in  the  mouth 
for  several  minutes  before  the  bitter  is  taken.  Yerba  santa  is 
itself  bitter  and  very  astringent.  It  contains  tannic  acid  in 
abundance,  and  it  is  largely  by  forming  the  insoluble  tannate  that 
it  lessens  the  bitterness  of  quinine  and  other  alkaloids. 

CHARCOAL 

Animal  charcoal  (carbo  animalis)  is  prepared  from  bones, 
and  85  per  cent,  of  it  consists  of  mineral  matter.  It  is  called 
"bone-black."  Purified  animal  charcoal  is  bone-black  boiled 
with  hydrochloric  acid  and  washed  thoroughly  with  water.  It 
is  almost  pure  carbon.  Wood  charcoal  (carbo  ligni)  is  prepared 
from  soft  wood;  it  is  nearly  pure  carbon.  Dose  of  charcoal, 
15  to  60  grains  (i  to  4  gm.).  The  larger  dose  makes  a  tablespoon- 
ful  and  for  intestinal  infections  should  be  given  four  times  a  day 
mixed  with  cereal  or  other  thick  liquid. 

Purified  animal  charcoal  possesses  the  power,  in  a  high  degree, 


110  PHARMACOLOGY  AND   THERAPEUTICS 

of  adsorbing  organic  colors,  hence  is  used  largely  in  pharmacy 
and  the  arts  for  decolorizing,  as  in  the  refining  of  sugar  and 
petroleum.  It  has  a  strong  affinity  for  bacterial  toxins,  and  has 
been  used  with  success  in  dysentery,  cholera,  and  other  intestinal 
infections.  It  has  also  a  certain  amount  of  power  to  remove 
certain  resins,  bitter  principles,  and  alkaloids  from  their  solu- 
tions, and  Lebourdais  has  in  this  way  recovered  digitalin,  colo- 
cynthin,  strychnine,  quinine,  and  other  active  principles.  Owing 
to  this  property,  it  has  been  proposed  as  a  remedy  in  mushroom 
poisoning,  arsenic  poisoning,  strychnine  poisoning,  etc.  Un- 
fortunately, this  property  of  adsorption  cannot  be  depended 
upon.  Wood-charcoal  and  bone-black  are  very  inferior  as  ad- 
sorbents. 

In  medicine,  wood-charcoal  has  been  used  in  flatulency  be- 
cause of  its  known  power  of  adsorbing  gases.  But  when  satu- 
rated with  liquid,  it  loses  this  power  of  gas  adsorption,  hence 
in  fermenting  stomach  contents  is  of  little  or  no  value.  In  the 
study  of  the  stools  it  is  much  employed  in  timing  the  passage 
through  the  alimentary  tract.  A  dose  of  30  grains  (2  gm.) 
given  with  a  meal  will  color  the  stool  resulting  from  that  meal 
black  or  gray -black.  (See  next  article.) 

KAOLIN— FULLERS'  EARTH 

These  are  silicates  with  powerful  adsorptive  properties. 
They  have  been  employed  locally  as  applications  to  wounds  and 
infected  mucous  membranes,  especially  in  diphtheria  and  ozena. 
Hektoen  and  Rappaport  found  that  the  dry  powder  of  kaolin 
blown  into  the  nose  several  times  a  day  for  3  or  4  days  removed 
not  only  diphtheria  bacilli  but  practically  all  the  nasal  bacteria. 
In  the  intestinal  tract  kaolin  has  been  employed  to  adsorb  toxins 
as  in  ptomaine  and  food  poisoning,  to  delay  ferment  activity,  and 
in  conjunction  with  animal  charcoal  to  adsorb  bacteria  and  check 
bowel  movements  in  the  treatment  of  severe  diarrheal  conditions,  as 
in  dysentery  and  cholera.  Hess  found  fullers'  earth  of  more  value 
than  kaolin  in  the  intestinal  disorders  of  infants,  and  Peterson 
noted  that  it  had  a  much  greater  retarding  influence  on  the  pro- 
teolytic,  diastatic  and  lipolytic  activities  in  intestinal  contents. 
In  cholera  and  dysentery  Wolff- Eisner  recommends  a  tablespoon- 
ful  each  of  kaolin  and  charcoal  mixed  with  oatmeal  gruel  three 
times  a  day,  and  Stumpff  uses  4  ounces  (i20gm.)  in  4  ounces  (120 
c.c.)  of  water  every  three  hours.  If  it  is  not  well  taken  thus,  he 
ices  it  and  gives  one  dram  (4  gm.)  every  two  minutes.  Fantus 
experimented  with  alkaloids  and  concluded  that  fullers'  earth 
has  decided  antidotal  value  for  morphine,  cocaine,  nicotine  and 


EMETICS  III 

ipecac;  less  for  strychnine  and  aconitine,  and  none  for  colchicine. 
He  noted  that  the  adsorptive  properties  varied  greatly  in  com- 
mercial preparations.  Fullers'  earth  is  known  as  terra  silicea  puri- 
ficata.  For  kaolin  poultice,  cataplasma  kaolini,  see  Counterirri- 
tants. 

EMETICS 

These  are  drugs  employed  to  induce  vomiting.  To  produce 
emesis  requires  the  coordination  of  several  mechanisms,  the 
following  actions  being  necessary:  viz.,  closure  of  the  pylorus, 
opening  of  the  cardia,  setting  or  contraction  of  the  diaphragm, 
and  contraction  of  the  abdominal  muscles.  If  the  pylorus  re- 
mains open,  the  result  is  "retching."  The  coordination  is  pre- 
sided over  by  the  vomiting  center  situated  in  the  medulla 
oblongata.  This  center  is  highly  sensitive  to  certain  sensory 
impulses  from  the  stomach,  and  is  also  capable  of  being  directly 
stimulated  by  certain  substances  in  the  circulating  blood.  The 
emetic  measures  in  common  use  may  be  divided  into  the  local  or 
reflex  emetics  and  the  central  emetics. 

1.  The  reflex  emetics  act  by  irritating  the  throat  or  stomach, 
and  are:   tickling  the  throat  with  a  feather,  or  sticking  the  finger 
down  the  throat,  or  swallowing  one  of  the  following:    a  large 
draft  of  lukewarm  water;  alum,  30  grains  (2  gm.);  copper  sul- 
phate,  10  grains  (1.7  gm.);  zinc  sulphate,   15  grains  (i  gm.); 
ipecac,   15  grains  (i  gm.);  tartar  emetic,  2  grains  (0.13  gm.); 
yellow  sulphate  of  mercury  or  turpeth  mineral,  2  grains  (0.13 
gm.);  mustard,  one  tablespoonful  (about  10  gm.).     The  drugs 
mentioned  are  all  local  irritants  and  systemic  poisons,  and  may  do 
great  harm  if  vomiting  fails  to  come  on;  hence  the  dose  should  not 
be  repeated.     (See  Ipecac.) 

2.  The  only  central  emetic  in  common  use  is  apomorphine 
hydrochloride,  apomorphine  being  an  alkaloid  derived  from  mor- 
phine by  dehydration.     It  is  soluble  in  40  parts  of  water  or  alco- 
hol, deteriorates  and  turns  green  on  exposure  to  light  and  air,  and 
is  considered  unfit  for  use  if  on  being  shaken  with  a  little  water  it 
imparts  at  once  an  emerald-green  tint.     The  emetic  dose  by 
hypodermatic  is  y1^  grain  (0.006  gm.),  and  the  expectorant  dose  is 
sV  grain  (0.002  gm.). 

Quite  quickly  after  a  hypodermatic  injection  of  apomorphine 
nausea  comes  on,  and  then,  in  about  five  minutes,  copious  vomit- 
ing. The  drug  is  not  at  all  excreted  into  the  stomach,  and  it 
acts  upon  the  center  directly.  Smaller  closes  are  expectorant, 
increasing  and  fluidifying  the  bronchial  mucus,  probably  by  a 
nauseant  action.  Small  doses  are  said  to  have  a  mild,  morphine- 
like  effect  in  promoting  sleep;  but  in  the  author's  tests  on  16 


112  PHARMACOLOGY   AND   THERAPEUTICS 

patients  for  several  successive  nights,  though  3V  grain  (0.003 
gm.)  proved  hypnotic,  every  patient  was  nauseated. 

Therapeutics  of  Emetics. — i.  To  empty  the  stomach — as 
in  acute  indigestion,  alcoholism,  the  ingestion  of  poisons,  etc. 

2.  To  remove  an  obstruction  from  the  esophagus  or  respira- 
tory passages. 

3.  To  loosen  a  ball- valve  gall-stone  in  the  biliary  passages 
(nature's  way). 

4.  To  relieve  spasm  or  marked  congestion  in  the  respiratory 
passages,  as  in  croup  or  severe  asthma. 

ANTEMETICS 

These  are  remedies  designed  to  check  nausea  and  vomiting 
In  the  treatment  of  nausea  and  vomiting  the  recumbent  positioi 
should  be  maintained.  The  antemetics  are: 

1.  Antacids,  to  check  hyperacidity;  especially  sodium  bicar- 
bonate, 20  grains  (1.3   gm.),  and  milk  of  magnesia,  2  drams  (8 
gm.);    or  to   check  acidosis,   large   amounts   of    sodium  bicar- 
bonate. 

2.  Carminatives. — Champagne,    brandy,    chloroform    water, 
essence  of  ginger,  spirit  of  peppermint,  menthol,  etc.     In  alcoholic 
nausea  and  vomiting  strong  hot  carminative  mixtures  are  indi- 
cated.    (See  Alcohol.) 

j.  Protectives — which  mechanically  prevent  irritation  of  the 
mucous  membrane,  as:  bismuth  subnitrate,  bismuth  subcar- 
bonate,  bismuth  subgallate,  and  cerium  oxalate,  dose  of  each, 
30  grains  (2  gm.). 

4.  Local  sedatives,  those  which  depress  the  sensory  nerve- 
endings:    Tincture  of  belladonna,  15  minims  (i  c.c.),  atropine 
sulphate,  T^j  grain  (0.0006  gm.),  cocaine  hydrochloride,  \  grain 
(0.015  gm.),  orthoform,  5  grains  (0.3  gm.),  anesthesin,  5  grains 
(0.3  gm.),  phenol,  3  grains  (0.2  gm.),  and  cracked  ice. 

5.  Central  sedatives. — Bromides,  chloral  hydrate,  chloretone, 
codeine,  morphine,  sulphonal,  veronal,  and  to  some  extent  other 
narcotics. 

6.  Counter  irritants  to  the  epigastrium,  as  a  hot-water  bag, 
an  ice-bag,  a  mustard  plaster,  or  the  actual  cautery. 

The  nausea  of  pregnancy  and  that  of  seasickness  are  espe- 
cially resistant  to  treatment.  In  pregnancy,  alkalies  given  at 
the  height  of  digestion  or  before  going  to  bed,  and  sometimes 
a  light  breakfast  before  arising,  may  be  effective.  Atropine  or 
bromides  or  cerium  oxalate  in  large  doses  may  also  be  tried. 
Frequently  no  measures  are  entirely  satisfactory.  Persistent 
vomiting  in  pregnancy  is  a  serious  toxic  manifestation,  usually 


ASTRINGENTS  113 

requiring  the  termination  of  the  pregnancy.  The  cause  of  the 
vomiting  may  be  acidosis,  and  this  is  an  indication  for  abundance 
of  alkalies  and  carbohydrate  food. 

In  seasickness  the  recumbent  position  on  deck,  with  eyes  pro- 
tected so  that  the  rolling  of  the  vessel  is  not  seen,  is  often  effective. 
Another  effective  measure  is  thorough  purgation  with  calomel 
or  compound  cathartic  pills  before  sailing,  and  every  two  or 
three  days  during  the  voyage.  The  avoidance  of  much  liquid, 
such  as  soup,  and  of  tobacco,  is  also  recommended.  Bromides, 
chloral  hydrate,  veronal,  chloretone,  champagne,  and  iced 
brandy  are  employed  with  varying  success.  A  much-vaunted, 
and  at  times  an  exceedingly  satisfactory,  prophylactic  remedy  is 
strychnine  sulphate,  yi^  grain  (0.0005  gm-)>  and  hyoscine  hydro- 
bromide,  ^7  grain  (0.00025  gm.),  every  hour  for  five  doses  before 
sailing,  and,  if  necessary,  repeated  every  day  during  the  trip. 
A  hypodermic  of  strychnine  sulphate,  3^  grain  (0.002  gm.), 
and  atrophine  sulphate,  y^g-  grain  (0.0006  gm.),  will  sometimes 
bring  about  a  striking  improvement  in  the  patient's  comfort. 

ASTRINGENTS 

These  are  drugs  which  tend  to  shrink  mucous  membranes  or 
raw  tissues.  Astringents  produce  their  effects:  (i)  by  con- 
striction of  arterioles,  as  epinephrine  and  cocaine;  (2)  by  ab- 
straction of  water,  as  glycerin  and  alcohol;  and  (3)  by  chemic 
precipitation  of  the  superficial  layers  of  protein,  as  the  metallic 
and  vegetable  astringents. 

The  most  employed  metallic  astringents  are:  Alum,  silver 
nitrate,  ferric  chloride,  ferric  subsulphate  (Monsell's  salt),  zinc 
sulphate,  and  copper  sulphate.  (See  Metals.) 

Potassium  chlorate  in  saturated  aqueous  solution  (i  :  16)  is 
employed  in  relaxed  sore  throat  and  in  stomatitis,  especially  that 
from  mercury;  but  where  there  is  ulceration  its  solutions  are 
quite  irritant.  Taken  internally  it  is  believed  by  some  to  be  a 
specific  in  ulcerative  stomatitis,  Holt,  for  instance,  recommending 
2  grains  (0.13  gm.),  every  hour  the  first  day,  then  every  2  hours. 
Bachem  (1912)  gave  i  ounce  (30  gm.)  daily  for  six  weeks  to 
pups,  and  there  was  no  effect  on  growth  rate,  kidneys,  stomach, 
or  blood.  The  drug  was  rapidly  eliminated  in  the  urine,  and 
acted  as  any  other  indifferent  salt.  Loevenhart  in  his  Harvey 
Society  Lecture,  1914,  stated  that  it  does  not  give  up  its  oxy- 
gen in  the  body  and  is  excreted  unchanged  in  the  urine,  yet 
it  is  capable  of  causing  severe  irritation  of  the  gastro-intestinal 
tract,  methemoglobinemia,  and  albuminuria.  Buri  states  that  this 
takes  very  large  doses.  Fifteen  grains  (i  gm.)  have  caused  death 


114  PHARMACOLOGY   AND   THERAPEUTICS 

in  a  child;  i  ounce  (30  gm.)  has  been  taken  without  symptoms. 
Mercier  (1902)  reports  death  in  a  child  of  three  years  eighteen 
hours  after  taking  "a  pinch  or  two"  of  the  chlorate.  At  autopsy 
the  blood  and  bone-marrow  had  a  prune- juice  appearance  and 
contained  methemoglobin ;  the  bladder  was  filled  with  dark 
brown  urine.  The  treatment  for  poisoning  is  lavage,  trans- 
fusion, and  measures  to  overcome  shock. 

Potassium  chlorate  mixed  dry  with  sulphur,  hypophosphites, 
and  oxidizable  organic  matters  is  likely  to  explode.  In  the 
form  of  tablets  it  has  frequently  caused  fire  on  contact  with  sul- 
phur matches. 

The  vegetable  astringents  contain  either  resins  or  tannic 
acid.  The  resinous  astringents  are  myrrh,  a  tincture  of  which, 
diluted  with  water,  is  used  for  soft  and  bleeding  gums,  and 
hydrastis,  whose  tincture,  diluted  with  water,  is  used  locally 
in  vaginitis  and  urethritis. 

The  tannic  acid  astringents  are:  blackberry  root  (rubus), 
catechu,  galls,  gambir,  kino,  rosa  gallica,  sumac  fruit  (rhus 
glabra),  and  witch-hazel  bark  (hamamelis).  They  have  dropped 
largely  out  of  use  and  their  only  official  preparations  are  the 
tincture  of  kino,  5  per  cent.,  and  the  compound  tincture  of  gambir, 
dose  of  each,  30  minims  (2  c.c.).  A  blackberry  brandy  or  cordial 
is  employed  by  the  laity  in  diarrhea. 


TANNIC   ACID   OR  TANNIN    (Acidum  Tannicum) 

This  substance  is  prepared  from  nutgalls.  It  is  slowly  but 
completely  soluble  in  less  than  its  own  weight  of  water  or  alcohol, 
and,  with  the  aid  of  heat,  in  its  own  weight  of  glycerin.  It  is 
used  locally  in  5  to  20  per  cent,  preparations,  or  internally  in 
dose  of  5  grains  (0.3  gm.).  The  ointment  and  the  glycerite  are 
of  20  per  cent,  strength.  The  troches  contain  i  grain  (0.06  gm.) 
in  each.  Tannic  acid  is  incompatible  with  alkaloidal  salts, 
metallic  salts  (such  as  mercuric  chloride),  lime-water,  gelatin, 
and  protein.  The  precipitation  of  the  gelatin  and  proteins  of 
hides  is  "tanning,"  and  changes  the  hides  into  leather.  In  like 
manner  tannic  acid  renders  insoluble  the  coatings  of  gelatin 
capsules  and  pills. 

Its  astringency  depends  upon  its  power  to  precipitate  the 
proteins  of  the  superficial  cells,  thus  causing  shrinking  of  the 
tissues  and  stoppage  of  secretion.  It  checks  small  hemorrhages, 
/.  e.,  is  hemostatic  or  styptic,  by  coagulating  the  blood.  In  the 
stomach  it  precipitates  the  proteins  of  the  food,  but  these  re- 
dissolve  in  the  gastric  juice.  Its  effect  on  mucous  membranes 
is  to  check  secretion.  Strasburger  believes  that  the  lessening  of 


ANTHELMINTICS  115 

intestinal  mucus  by  astringents  results  in  a  great  diminution  in 
the  number  of  bacteria  in  the  feces.  In  the  intestines  free  tannic 
acid  is  constipating,  but  it  soon  changes  to  sodium  tannate  and 
then  to  sodium  gallate,  which  is  not  astringent.  It  is  absorbed 
and  excreted  as  sodium  gallate,  and  has  no  astringent  or  styptic 
power  after  absorption.  Because  of  the  rapid  disappearance  of 
tannic  acid  from  the  intestines,  preparations  of  the  vegetable 
drugs  are  preferred  in  diarrhea,  the  colloid  and  other  extractive 
vegetable  matters  tending  to  retard  the  chemic  changes  and  ab- 
sorption of  the  tannic  acid.  If  in  too  concentrated  form,  tannic 
acid  is  an  irritant. 

Therapeutics. — i.  To  harden  the  skin,  as  in  threatened  bed- 
sore. 

2.  As  a  gargle  or  swab  in  relaxed  sore  throat. 

3.  As  a  hemostatic  for  small  accessible  hemorrhages. 

4.  As  chemic  antidote  in  poisoning  by  alkaloidal  and  metal- 
lic salts,  especially  those  of  antimony,  with  which  it  forms  a  very 
insoluble  substance. 

5.  In  the  form  of  suppository,  each  containing  5  grains  (0.3 
gm.),  in  prolapse  of  the  rectum  or  bleeding  internal  hemorrhoids. 

6.  In  diarrhea-  the  vegetable  astringents. 

Tannigen  (diacetyl tannin),  tannoform  (formaldehyde-tannin), 
tannopin  (hexamethylenamine-tannin),  and  tannalbin  (egg-al- 
bumin tannate)  are  all  compounds  marketed  for  diarrhea.  The 
claims  are  made  for  them  that  they  do  not  act  in  the  stomach, 
but  liberate  the  tannic  acid  in  the  intestines.  Dose  of  each, 
10  grains  (0.7  gm.). 

Styptics. — The  astringent  remedies  especially  used  as  styptics, 
that  is,  to  check  hemorrhage,  are:  Solutions  of  epinephrine, 
antipyrine,  alum,  silver  nitrate,  ferric  chloride,  ferric  sulphate, 
and  ferric  subsulphate  (Monsell's  solution),  very  hot  water,  very 
cold  water,  glycerite  of  tannic  acid,  and  2  per  cent,  acetic  acid. 

ANTHELMINTICS 

An  anthelmintic  is  a  remedy  designed  to  promote  the  death  or 
expulsion  of  intestinal  worms.  Most  of  the  remedies  are  also 
toxic  to  man,  and  since  the  anthelmintic  is  to  attack  the  worm, 
rather  than  the  patient,  the  dose  must  be  as  large  as  one  dare 
risk,  whether  the  patient  is  a  child  or  an  adult. 

Before  the  administration  of  a  toxic  anthelmintic  it  is  custom- 
ary to  starve  the  patient  for  from  twelve  to  twenty-four  hours 
and  to  give  a  brisk  cathartic,  the  object  being  to  clean  out  the 
intestines  and  leave  the  worm  in  an  exposed  condition.  The 
dose  is  then  administered,  and  is  followed  in  four  or  five  hours  by 


Il6  PHARMACOLOGY   AND   THERAPEUTICS 

a  brisk,  rapidly  acting  cathartic,  such  as  castor  oil  or  salts,  to 
carry  out  the  worm.  Castor  oil  has  been  objected  to  on  the 
ground  that  an  oily  medium  will  promote  the  absorption  of  the 
poison  by  the  patient.  This  may  be  true,  especially  in  the  case 
of  oleoresin  of  male  fern,  if  rapid  evacuation  of  the  bowels  does 
not  take  place.  The  different  kinds  of  parasite  require  different 
kinds  of  treatment,  as  follows: 

1.  The   Pin-   or   Thread- worms    (Oxyuris  Vermicular  is).— 
These  are  tiny,  thread-like  organisms  which  live  in  great  abun- 
dance in  the  colon  or  the  adjoining  portion  of  the  ileum,  chiefly 
in  the  mucus.    As  they  do  not  cling  to  the  intestinal  wall,  they 
are  readily  carried  out  by  cathartics;  or,  as  they  are  very  vulner- 
able, may  be  attacked  by  colon  irrigations.     Occasionally  they 
penetrate  the  mucous  membrane  of  the  intestine  or  inhabit  the 
appendix,  and  then  they  cannot  be  dislodged. 

The  cathartics  mostly  employed  are  calomel  and  castor  oil. 
By  mouth  both  thymol  and  oil  of  chenopodium,  as  used 
for  hookworms,  have  proved  highly  effective.  A  number  of 
substances  are  used  for  colon  injection,  viz.,  the  infusion  of 
quassia,  lime-water,  a  solution  of  phenol,  0.25  per  cent.,  a  solution 
of  quinine  bisulphate,  i  :  2000,  a  solution  of  tannic  acid  or  alum, 
30  grains  (2  gm.)  in  one  pint  (480  c.c.),  and  soapsuds  containing 
\  ounce  of  the  oil  of  turpentine  to  a  quart.  The  astringents 
are  effective  not  only  by  shriveling  the  worms,  but  also  by  lessen- 
ing the  intestinal  mucus  in  which  the  worms  may  lodge.  The 
Hymenolepis  or  Tcenia  nana,  which  are  tiny  tape-worms,  are 
sometimes  taken  for  pin-worms. 

2.  The  Round-worms. — a.  The  common  round-worm,  Ascaris 
lumbricoides ,  grows  to  a  length  of  6  to  12  inches  or  even  more. 
They  usually  inhabit  the  small  intestine,  but  may  be  found  in 
the  colon  or  stomach,  and  have  been  known  to  stop  up  the 
common  bile-duct.     The  author  has  had  several  patients  who 
have  vomited  round-worms,  and  in  two  instances  drew  up  a  piece 
of  round-worm  through  a  stomach-tube.     These  must  have  been 
in  the  stomach.     They  may  be  the  cause  of  intestinal  hemorrhage. 
The  remedies  are: 

Chenopodium — see  under  "Hookworms." 

Santonin  (santoninum),  a  glucoside  from  santonica  (Levant 
wormseed),  dose,  2  grains  (0.12  gm.)  for  an  adult,  and  i  grain 
(0.06  gm.)  for  a  child  of  five  years.  Santonica,  ^  dram  (2  gm.), 
is  sometimes  taken  as  it  is  or  in  the  form  of  an  infusion.  Santonin 
is  highly  toxic,  and  death  has  occurred  from  5  grains  (0.3  gm.) 
in  an  adult,  and  3  grains  (0.2  gm.)  in  a  child.  The  symptoms  of 
poisoning  are  nausea,  vomiting,  and  central  stimulation.  The 
reflexes  are  increased,  and  there  may  be  headache,  dizziness, 


ANTHELMINTICS  117 

delirium,  hallucinations,  and  possibly  epileptiform  convulsions, 
followed  by  collapse  and  death.  A  peculiarity  of  santonin 
poisoning  is  partial  blindness,  accompanied  by  yellow  vision. 
Baxter  reports  lost  vision  in  a  girl  of  five  after  \  grain  (0.03  gm.). 
JellifTe  (1906)  reports  prolonged  convulsions,  followed  by  collapse, 
in  a  girl,  from  two  troches  followed  by  castor  oil  which  failed 
to  move  the  bowels.  After  this  she  was  blind,  very  restless,  and 
prostrated  for  three  weeks,  and  showed  signs  of  nephritis.  She 
became  a  permanent  epileptic. 

The  treatment  of  poisoning  is  lavage  of  the  stomach,  followed 
by  a  large  dose  of  Epsom  salts,  the  inhalation  of  ether,  and  the 
management  of  symptoms  as  they  arise.  The  central  stimulation 
must  be  handled  with  care  because  of  the  tendency  to  collapse. 

Santonin  has  come  into  notice  of  late  as  a  remedy  for  the  pains 
of  locomotor  ataxia  and  for  diabetes,  but  clinical  data  do  not 
justify  these  uses  of  so  dangerous  a  drug. 

Spigelia  (pink-root)  has  an  official  fluidextract,  dose,  60 
minims,  (4  c.c.).  It  is  frequently  given  with  senna  (fluidextract 
of  pink-root  and  senna),  the  senna  furnishing  the  required, 
though  rather  late,  cathartic  action.  In  poisoning  it  causes 
central  depression,  with  prostration,  stupor  or  coma,  muscular 
weakness,  incoordination,  and  collapse. 

b.  The  hookworms  (  Lncinaria  or  Necator  or  Ankylostoma 
americana)  are  treated  by  thymol  or  oil  of  chenopodium.  Thymol — 
Public  Health  Bulletin  No.  32  recommends  a  dose  of  Epsom 
salts  at  night,  followed  at  6  A.  M.  by  half  the  dose  of  thymol,  at 
8  by  the  other  half  of  the  thymol,  and  at  10  by  another  dose  of 
Epsom  salts.  This  treatment  is  repeated  once  a  week.  The  dose 
recommended  is  7^  grains  (0.5  gm.)  for  a  child  of  five  years,  and 
45-60  grains  (3  to  4  gm.)  for  an  adult,  given  in  5-grain  (0.3  gm.) 
capsules.  It  is  best  mixed  with  an  equal  weight  of  lactose  or 
sodium  bicarbonate.  Seidell  finds  insignificant  amounts  of 
thymol  in  the  feces  and  only  50  per  cent,  in  the  urine,  He 
notes  that  absorption  is  not  promoted  by  its  solution  in  oil. 

Thymol  has  also  been  employed  in  trichinosis,  both  while 
the  parasites  are  still  in  the  intestine  and  when  they  are  lodged 
in  the  muscles.  For  the  latter,  2  to  3  grains  (0.12-0.2  gm.)  in 
30  to  45  minims  (2-3  c.c.)  of  olive  oil  are  injected  subcutaneously 
daily.  Musgrave  recommends  thymol  for  irrigation  in  amebic 
colitis.  Thymol  has  in  several  instances  caused  fatal  poison- 
ing of  the  volatile  oil  type.  Death  has  resulted  from  15  grains 
(i  gm.)  in  a  child;  yet  in  adults  as  much  as  225  grains  (15  gm.) 
have  been  given  in  twelve  hours  (Bozzolo,  1912)  without  any 
toxic  effects. 

Oil,  of  Chenopodium. — Since   1915   much   has  been  written 


Il8  PHARMACOLOGY  AND  THERAPEUTICS 

about  the  great  efficacy  of  this  remedy  in  hookworm  disease, 
and  it  has  been  reported  of  fair  value  for  pin-worms,  round- 
worms,  whip-worms  and  even  tape-worms.  The  oil  is  constipat- 
ing and  the  consensus  of  opinion  is  that  it  should  be  given  in 
association  with  castor  oil.  An  acceptable  plan  is  as  follows:  A 
dose  of  Epsom  salts  or  castor  oil  in  the  morning  is  followed  by 
liquid  diet  for  the  whole  day.  The  next  day  a  dose  of  Epsom 
salts  or  castor  oil  is  administered,  and  one  hour  later  oil  of 
chenopodium,  5  to  8  minims  (0.3-0.5  c.c)  or  about  15  drops, 
in  a  capsule  or  dropped  on  sugar,  this  dose  being  repeated  twice 
at  one  or  two  hour  intervals,  i.  e.,  for  three  doses  in  all.  Two 
hours  after  the  last  dose,  i-i|  oz.  (30-45  c.c.)  of  castor  oil  con- 
taining from  30  to  45  minims  (2-3  c.c.)  of  chloroform  is  adminis- 
tered. The  chloroform  aids  in  the  paralysis  of  the  worms.  No 
food  is  taken  till  after  this,  when  a  cup  of  tea  may  be  allowed 
and  later  a  light  supper.  The  treatment  is  repeated  each  week. 
For  a  child  of  6  years  the  doses  are  half  the  above. 

A  number  of  cases  of  poisoning  have  been  reported,  but  very 
few  in  proportion  to  the  enormous  number  of  doses  given. 
Levy  collected  12  cases,  9  of  them  fatal  in  2  to  5  days.  The 
smallest  doses  (reported  by  Para'more)  were  4  drops  three  times 
a  day  for  7  doses  resulting  in  the  death  of  an  infant  of  one  year, 
and  6  drops  three  times  a  day  for  seven  doses  causing  severe 
poisoning  in  a  child  of  three  years,  with  recovery.  Coutant 
reports  poisoning  with  recovery  in  a  man  of  21  years  from  two 
doses  of  10  minims  (0.7  c.c.)  given  24  hours  apart.  Pole  reports 
recovery  of  a  child  of  two  years  after  two  teaspoonfuls  given  in 
one  afternoon.  The  symptoms  are  those  of  gastro-intestinal 
irritation  and  central  depression,  i.  e.,  nausea,  vomiting,  diarrhea, 
bloody  and  mucous  stools,  and  abdominal  cramps,  with  headache, 
drowsiness,  mental  and  physical  depression,  and  -collapse.  There 
maybe  tinnitus  aurium,  ataxia,  paralyses,  convulsions,  and  coma. 
Salant  and  Livingston,  1915,  state  that  the  toxicity  is  distinctly 
increased  by  starvation,  and  decreased  by  feeding  oils  or  carbo- 
hydrates. They  also  noted  cumulative  effects.  Ascaridole,  the 
active  principle  of  the  oil,  was  30  per  cent,  more  toxic  than  the 
oil.  They  have  shown  that  solutions  of  i  to  5000  and  i  to  10,000 
of  the  oil  cause  a  marked  decrease  of  tone  in  the  isolated  intestine 
of  rabbits,  both  muscle  and  nerve-endings  being  depressed;  also 
that  in  intact  animals  there  is  a  decline  in  tone  of  the  intestines 
and  a  depression  of  the  heart  muscle  and  the  vagus  center,  and 
an  unexplained  depression  of  the  respiration. 

In  poisoning  the  treatment  is  symptomatic.  Motter  advises 
that  inordinate  sleepiness  or  -depression  call  for  stoppage  of  the 
drug,  immediate  purgation  by  castor  oil,  and  central  stimulation, 
as  by  caffeine  and  strychnine. 


CATHARTICS  IIQ 

3.  The  tape-worms  seen  in  America  are  mostly  that  of  beef, 
T&nia  saginata;  that  of  fish,  Dibothriocephalus  latus;  and  the 
dwarf  tape-worm,  Hymenolepis  nana.  The  remedies  are  some- 
times called  teniacides  and  teniafuges.  The  favorite  remedy  is 
oleoresin  of  aspidium  (male-fern),  i  dram  (4  gm.)  in  capsules. 
Others  are  cusso,  %  ounce  (15  gm.)  in  infusion;  granatum  (pome- 
granate root  bark),  2  drams  (8  gm.)  in  infusion;  pepo  (pumpkin- 
seed),  ^  ounce  (15  gm.)  in  infusion;  kamala,  i  dram  (4  gm.) 
mixed  with  syrup;  oil  of  turpentine,  \  ounce  (15  c.c.),  and  chloro- 
form, i  dram  (4  c.c.).  Pelletierine ,  an  alkaloid  from  granatum, 
in  the  form  of  the  tannate,  dose,  4  grains  (0.25  gm.),  and  amor- 
phous filicic  acid,  one  of  the  constituents  of  male-fern,  dose,  10 
grains  (0.7  gm.),  are  also  employed.  Power  and  Salway  failed 
to  find  any  anthelmintic  properties  in  the  constituents  of  pumpkin- 
seed. 

Poisoning  by  aspidium,  granatum,  and  kamala  shows  in 
gastro-intestinal  irritation,  with  vomiting,  purging,  stupor, 
vertigo,  muscular  twitching,  collapse,  and  perhaps  irritation  of 
the  kidneys.  There  may  be  hemolysis  with  jaundice  (Grawitz). 
Hall  reports  a  fatal  case  from  male-fern  with  r^emorrhagic  areas 
in  the  upper  three  feet  of  intestine.  We  have  several  times  seen 
severe  gastro-enteric  irritation  with  vertigo  and  prostration 
result  from  the  hospital  "Early-Bird"  mixture.  This  consists 
of  pumpkin-seed,  2  drams  (8  gm.),  cusso  and  granatum,  each, 
i  dram  (4  gm.),  made  into  an  infusion,  to  which  are  added 
kamala,  i  dram  (4  gm.),  oleoresin -of  aspidium,  i  dram  (4  gm.), 
glycerin,  \  ounce  (15  c.c.),  mucilage  of  acacia,  \  ounce  (15  c.c.), 
and  water  to  make  the  total  amount  8  ounces  (240  c.c.).  After 
the  usual  preliminary  starvation,  this  quantity  is  taken  in  two 
drafts  two  hours  apart.  The  "early  bird"  usually  gets  the  worm. 

CATHARTICS 

A  cathartic  is  a  measure  designed  to  promote  defecation. 
Such  a  remedy  may  be  employed — (i)  In  cases  of  constipation; 
(2)  for  the  removal  of  irritating  or  otherwise  harmful  material 
from  the  intestines,  as  in  food-poisoning,  intestinal  putrefaction, 
and  some  forms  of  diarrhea;  (3)  for  general  depletion,  as  in 
plethoric  or  dropsical  states,  cerebral  congestion,  or  at  the  onset 
of  the  infectious  fevers. 

Constipation  is  a  condition  of  insufficient  frequency  of  de- 
fecation, or  of  insufficient  quantity  regardless  of  frequency,  or 
of  hardness  and  dryness  of  the  feces.  The  usual  number  of 
stools  in  a  day  is  one  or  two,  but  many  people  maintain  health 
though  they  habitually  depart  from  this  rule  in  a  marked  degree. 


120 


PHARMACOLOGY   AND   THERAPEUTICS 


Muscle 


AuerbochJs 


Vagus 


V 


Mol-or 


Splanchnic. 


1  nhibitory 


The  feces  are  normally  composed  of  food  residue,  bacteria,  secre- 
tions, and  products  of  chemic  and  bacterial  activities  in  the 
intestinal  canal.  In  some  cases  the  bacteria  form  as  much  as 
one-third  of  the  dried  feces  (Strasburger) . 

The    Mechanical   Factors   of   Defecation. — The  Small    In- 
testines.— The  peristaltic  wave  is  the  active  force  in  the  propul- 
sion onward  of  the  contents  of  the  small  intestine.    Its  stimulus 
depends  on  the  integrity  of  Auerbach's  plexus,  and  the  peristaltic 
movement  is  coordinated  and  purposeful.     It  involves  contrac- 
tion above  the  stimulating  object  and  relaxation  below  it.     The 
wave,  once  started,  is  propelled  from  muscle-fiber  to  muscle- 
fiber,  directly  or  through  nerve- 
fibrils,  and  the  wave-like  rather 
than  continuous  contraction  is 
insured  by  a  short  refractory 
period  of  the  muscle  (Magnus). 
Under  abnormal  stimuli,  as  by 
irritant    cathartics,    the     nor- 
mal, slow,  worm-like  peristaltic 
movement     may     become     a 
"peristaltic  rush"  (Meltzer  and 
Auer),  with  discharge  of  prac- 
tically the  whole    contents  of 
the    small    intestine    into    the 
cecum  in  a  very  short  time.     It 
is  probable  that  the  site  of  con- 
stipation is  rarely  in  the  small 

intestines,  except  possibly  in  the  neighborhood  of  the  ileocolic 
junction. 

The  Cecum  and  Colon. — These  form  a  great  reservoir  along 
which  the  contents  are  passed  very  slowly,  and  probably  in  a 
manner  different  from  that  in  the  small  intestines.  In  the 
cecum  and  ascending  colon  so  much  liquid  is  absorbed  that  by  the 
time  the  residue  reaches  the  transverse  colon  it  has  begun  to 
take  on  the  consistence  of  feces  (Roith).  Regular  antiperistalsis 
has  been  observed  in  cats  and  other  animals;  and,  as  shown  by 
the  x-ray  in  man,  it  takes  but  a  few  moments  for  a  rectal  in- 
jection to  reach  the  cecum. 

The  time  normally  required  for  the  passage  from  stomach-  to 
rectum  has  been  studied  under  the  x-ray  by  meals  mixed  with 
bismuth  salts.  For  the  first  portion  of  a  bismuth  meal  to  reach 
the  cecum  Hertz  found  the  average  time  to  be  four  and  a  half 
hours,  and  for  the  last  portion  nine  hours.  Satterlee  and  LeWald, 
in  27  cases,  found  two  hours  the  average  time  for  the  food  to 
reach  the  cecum,  only  one  hour  being  required  in  3  cases, 


•Sensory 


Fig.  2. — Chart  showing  local  and 
central  innervation  of  the  small  intes- 
tine (after  Dixon) 


CATHARTICS  121 

and  the  longest  time  being  five  hours.  In  9  cases  it  took  from 
four  to  seven  hours  for  complete  emptying  of  the  small  intestine. 
Hertz  found  that  the  hepatic  flexure  is  reached  in  six  and  a  half 
hours,  the  splenic  flexure  in  nine  hours,  the  iliac  colon  in  eleven 
hours,  the  pelvic  colon  in  twelve  hours,  and  the  lower  part  of  the 
pelvic  colon  in  eighteen  hours.  At  this  point  is  the  pelvirectal 
reservoir  in  which  the  contents  remain  until  defecation.  Bismuth 
meal  pictures  do  not,  however,  tell  the  rate  of  a  normal  mixed 
meal.  In  a  patient  with  an  ileal  artificial  anus,  Lynch  found  that 
a  mixed  meal  appeared  in  seven  hours,  while  the  bismuth  meal 
did  not  appear  for  twelve  hours. 

On  arising  in  the  morning  or  on  eating  breakfast,  as  observed 
by  Hertz  with  the  x-ra.y,  peristalsis  begins  in  the  colon  and  car- 
ries the  feces  into  the  rectum.  When  the  rectum  becomes  dis- 
tended, the  subject  receives  subjective  sensations  of  a  desire  to 
go  to  stool.  At  stool  the  abdominal  muscles  are  contracted  so 
that  more  material  is  forced  into  the  rectum  and  into  the  anal 
canal.  This  results  in  the  defecation  reflex,  with  relaxation  of 
the  anal  sphincters,  colon  peristalsis,  and  renewed  contraction  of 
the  abdominal  muscles.  At  stool  the  whole  large  intestine  from 
splenic  flexure  onward  is  emptied,  a  relatively  long  column  of 
feces  resulting.  In  addition,  while  the  act  of  defecation  is  taking 
place,  a  portion  of  the  contents  of  the  transverse  colon  may  move 
into  the  descending  colon  and  pass  out.  The  shape  and  the  size 
of  feces  as  passed  are  largely  determined  by  their  consistence  and 
by  the  irritability  of  the  anal  canal,  and  not  by  strictures  high  up 
in  the  rectum. 

According  to  the  above,  the  stool  normally  contains  the  food- 
products  which  have  reached  the  splenic  flexure.  Hence  the 
first  portions  of  a  meal  eaten  nine  or  ten  hours  before  will  normally 
appear  in  the  stool,  while  a  portion  of  the  residue  from  that  meal 
will  not  appear  until  the  next  stool.  If  there  is  but  one  stool  a 
day,  therefore,  it  will  normally  contain  material  from  the  food 
eaten  as  much  as  thirty-four  hours  before.  Hence,  Hertz  con- 
cludes that  if,  after  a  morning  defecation,  the  residue  of  food 
taken  at  4  P.  M.  does  not  appear  in  the  feces  the  second  morning 
after,  there  is  constipation.  To  check  off  the  material  of  a  given 
meal,  it  is  customary  to  give  a  capsule  of  5  grains  (0.3  grru)  of 
carmine,  or  half  a  dozen  lozenges  of  charcoal,  about  30  grains 
(2  gm.),  with  the  meal.  These  color  the  feces  from  that  meal 
pink  or  gray-black  respectively.  (Excellent  reference  works  on 
the  actions  of  the  bowels  are:  Hertz,  " Constipation  and  Allied 
Intestinal  Disorders,"  1909;  W.  B.  Cannon,  "The  Mechanical 
Factors  of  Digestion,"  1911.) 

Griping  or  cramp  is  a  condition  often  produced  by  cathartics. 


122  PHARMACOLOGY   AND   THERAPEUTICS 

It  is  probably  caused  by  a  spasmodic  oontractk>n  at  the  site  of 
an  irritant,  instead  of  coordinated  peristalsis.  The  work  of 
Hertz  suggests  that  the  distention  behind  the  contracted  ring 
may  be  the  cause  of  the  pain. 

CATHARTIC   MEASURES 

Cathartic  measures  are  laxative  when  employed  to  produce 
soft  stools  of  about  normal  frequency,  and.  purgative  when  em- 
ployed to  produce  copious  soft  or  liquid  movements.  A  hydra- 
gogMe  is  any  remedy  that  will  result  in  copious  watery  stools. 
The  term  aperient  is  sometimes  employed  for  any  cathartic,  but 
especially  for  a  saline. 

The  term  cholagogue  was  formerly  applied  to  certain  sub- 
stances which  were  thought  to  increase,  the  production  of  bile. 
The  amount  of  bile  may  be  increased  by  large  amounts  of  ox-gall 
or  bile-salts  administered  by  mouth,  and  to  a  slight  extent  by 
salicylic  acid.  It  is  also  increased  by  the  injection  of  secretin 
into  the  blood  (Starling).  But  pharmacologic  research  has  shown 
that  we  have  no  effective  agents  which,  in  therapeutic  amounts, 
have  this  action,  so  the  term  had  best  be  abandoned. 

Cathartic  measures  include  habit  formation,  response  to  the 
desire  to  defecate,  exercise,  massage,  food,  and  drugs. 

1 .  Habit  formation  is  the  establishment  of  a  regular  time  for 
the  daily  stool.     Usually  this  time  is  just  after  breakfast,  both 
because  this  is  a  convenient  time  and  because  the  activity  of 
dressing  and  the  taking  of  food  both  tend  to  stimulate  colon 
peristalsis.     Even  when  there  is  no  desire  to  defecate  it  is  ad- 
visable to  make  the  attempt;  for  the  voluntary  effort  may  force 
some  feces  into  the  rectum  and  so  result  in  the  proper  subjective 
sensations  which  bring  about  the  defecation  reflexes.     The  after- 
breakfast  smoke  tends  to  promote  defecation. 

2.  That  response  to  the  desire  to  defecate  is  important  is  indi- 
cated by  Hertz's  observation  that  the  rectum  accommodates 
itself  to  the  presence  of  a  fecal  accumulation,  so  that  if  the  desire 
is  not  responded  to,  it  will  pass  away  and  the  defecation  reflex 
become  impaired.     Many  persons  have  become  habitually  con- 
stipated  because   their   occupation   interfered   with  defecation. 
Women  in  business,  for  example,  often  suppress  the  desire  to 
defecate  rather  than  pass  a  number  of  men  to  reach  the  toilet. 

3.  The   exercises   of   value    are:    walking,    running,    rowing, 
horseback  riding,  tennis,  golf,  gymnastics,  and  special  abdominal 
exercises.     Such  are:  bending  the  body  forward  or  backward, 
or  from  side  to  side;  lying  on  the  back  and  raising  the  legs  to  a 
right  angle  with  the  trunk,  or  raising  the  trunk  to  a  right  angle 


CATHARTIC   MEASURES  123 

with  the  legs,  etc.  It  must  be  noted  that  there  are  many  persons 
who  live  a  sedentary  life  yet  are  not  constipated,  and  that  many 
athletes  and  gymnasts  have  habitual  constipation.  In  fact, 
exercise  is  frequently  of  value  only  so  far  as  it  promotes  appe- 
tite and  thus  increases  the  amount  of  food  eaten. 

4.  Massage  may  be  either  superficial  or  deep.     It  may  be 
performed  by  active  kneading  in  the  direction  of  the  colon,  by  a 
rotary  motion  of  the  abdominal  wall  over  the  viscera,  by  vibra- 
tory massage  with  the  hands  or  a  machine,  or  by  rolling  a  cannon- 
ball  or  ball  of  clay  covered  with  leather  or  chamois  over  the 
abdomen  from  cecum  to  sigmoid  below  the  navel  in  the  direction 
of  the  hands  of  a  clock.     Such  a  clay  ball  may  be  heated. 

5.  Foods. — There  is  no  sharp  dividing-line  between  food  and 
drugs,  certain  substances  acting  as  food  or  as  drug  according  to 
circumstances.     A   substance   cannot   serve   as   nutriment   and 
act  as  a  cathartic  at  the  same  time;  for  if  it  is  absorbed,  it  does 
not  act  as  a  cathartic,  and  vice  versa.     Those  who  habitually 
undereat  will  be  constipated. 

Foods  tend  to  promote  bowel  movements  by — (i)  Chemic 
stimulation,  as  of  sugars  and  fruit  acids  and  their  salts,  and  di- 
gestive products,  such  as  proteins,  amino-acids,  soaps,  etc;  (2)  me- 
chanical stimulation,  as  by  seeds  or  husks;  (3)  increasing  the 
bulk  of  intestinal  contents,  as  by  cellulose,  skins,  etc.,  and  un- 
absorbed  oils  and  fats  or  their  soaps. 

Foods  of  too  ready  digestibility  are  constipating.  Of  enor- 
mous importance  (Hertz)  is  cellulose;  in  fact,  Rubner  states  that 
"in  the  absence  of  cellulose  from  food  almost  everything  is  ab- 
sorbed." Fruits  and  vegetables  rich  in  cellulose  pass  into  the 
intestines  as  paste  and  stimulate  peristalsis;  meat,  eggs,  and 
milk  pass  as  liquids  and  so  favor  segmentation,  but  not  peristalsis 
(Cohnheim).  Hertz  reports  that  of  the  dry  substance  of  meat, 
eggs,  white  bread,  and  rice,  only  5  per  cent,  appeared  in  the  feces; 
while  of  the  dry  substance  of  green  vegetables  and  brown  bread 
15  per  cent.,  and  of  the  dry  substance  of  carrots  and  turnips  20 
per  cent.,  appeared  in  the  feces.  The  feces  of  a  mixed  diet  gave 
100  gm.  of  water  and  35  gm.  of  dry  substance;  the  feces  of  a 
vegetable  diet  gave  260  gm.  of  water  and  75  gm.  of  dry  substance. 

Vegetables  and  salads  mostly  contain  fibrous  tissue  and  cellu- 
lose. Many  vegetables  are  as  much  laxative  as  nutritive.  Salad 
dressing  contains  oil,  which  tends  to  be  laxative. 

Cereals  contain  cellulose.  Oatmeal  is  especially  laxative, 
because  of  the  presence  of  indigestible  husks.  Oatmeal  water  is 
even  said  to  be  more  laxative  than  waters  made  from  other  cereals, 
but  no  soluble  laxative  principle  has  been  isolated,  and  the  water 
lacks  the  special  laxative  agent  (the  husks)  of  the  oatmeal  itself. 


124  PHARMACOLOGY  AND  THERAPEUTICS 

Fruits  contain  sugar,  cathartic  acids  or  salts,  indigestible 
structural  parts  (fiber,  cellulose,  skins,  etc.),  seeds,  and  non- 
absorbable  colloid  pectin  bodies.  Those  most  frequently  con- 
sidered laxative  are  prunes,  figs,  and  dates;  but  an  apple,  an 
orange,  a  banana,  or  some  grapes  at  bedtime  will  often  insure  the 
morning  stool.  The  morning  coffee  also  promotes  defecation. 

Water,  in  copious  draughts,  may  act  as  a  laxative  in  persons 
who  take  too  little  liquid,  but  normally  it  merely  serves  to  acti- 
vate the  kidneys.  (See  Diuretics.) 

6.  Drugs. — These  are  usually  administered  by  mouth,  but  a 
few  may  be  employed  subcutaneously,  and  some  are  used  by 
rectum  in  the  form  of  enemata  and  suppositories.  Cathartic 
drugs  may  be  loosely  classified  as: 

A.  Those  acting  by  a  selective  affinity  for  the  nervous  struc- 
tures. 

B .  Those  acting  mechanically  to  give  bulk  and  soft  consistency 
to  the  feces. 

C.  Those  acting  as  bowel  irritants. 

D.  The  saline  cathartics — which  have  a  special  action. 

A.   CATHARTICS  ACTING  BY  SELECTIVE  AFFINITY 

In  Class  A  we  have:  Physostigmine  salicylate,  dose,  ^  grain 
(o.ooi  gm.),  which  stimulates  the  ends  of  the  vagus  or  motor 
nerves  of  the  intestines;  pituitary  extract,  which  stimulates  the 
muscles;  and  apocodeine,  dose,  ^  grain  (0.03  gm.),  which  de- 
presses the  ends  of  the  splanchnic  or  inhibitory  nerves,  thus 
freeing  the  bowel  from  inhibition  and  increasing  its  motor 
activity. 

B.  MECHANICAL  AGENTS  TO  GIVE  BULK  AND  SOFT  CONSIST- 
ENCY TO  THE  FECES 

Sulphur  increases  the  bulk  of  the  feces  and  makes  the  stool 
soft.  It  is  partly  changed  by  the  proteins  of  the  alimentary 
tract  into  sulphides,  sulphites  and  sulphates,  which  are  mildly 
stimulating  to  peristalsis.  The  intestinal  gases  are  increased 
in  their  sulphureted  hydrogen  constituent,  and  the  feces  may 
have  a  sulphuret  odor.  Some  of  the  products  are  absorbed,  as 
shown  by  the  increase  of  sulphates  in  the  urine. 

Sulphur,  cream  of  tartar  (potassium  bitartrate),  and  molasses 
is  a  favorite  household  "spring  medicine,"  and  tablets  may  be 
had  containing  various  proportions  of  cream  of  tartar  and  sul- 
phur. For  the  blood,  in  acne,  it  is  given  in  the  form  of  calcium 
sulphide,  dose,  i  grain  (0.006  gm.).  Precipitated  sulphur  and 
potassa  sulphiirala  are  also  used  in  lotions  for  acne.  In  scabies 


CATHARTIC  MEASURES  125 

sulphur  is  sprinkled  in  the  bed,  and  also  applied  to  the  skin  in 
ointment  form.  For  room  disinfection  it  is  burned  to  produce 
sulphur  dioxid  (SO2). 

There  are  three  official  forms  of  sulphur,  viz. : 

Sulphur  sublimatum  (sublimed  sulphur,  flowers  of  sulphur), 
which  is  preferred  as  a  laxative,  as  it  contains  free  sulphurous 
acid  and  is  gritty. 

Sulphur  lotum  (washed  sulphur),  which  is  freed  from  acid 
by  washing  with  ammonia,  but  is  gritty.  Its  15  per  cent,  oint- 
ment (unguentum  sulphuris)  is  official. 

Sulphur  pr&cipitatum  (precipitated  sulphur),  prepared  by 
precipitation  from  a  solution  of  alkaline  sulphide.  It  is  soft  and 
not  gritty,  and  is  preferred  in  lotions. 

Agar  (A  gar -agar}  is  a  form  of  hemi-cellulose  prepared  from 
several  species  of  seaweed.  It  has  the  property  of  absorbing 
water  to  form  a  jelly-like  material.  After  heating  1.5  parts  of  it 
with  100  of  water  it  cools  to  a  stiff  jelly,  which  is  used  extensively 
in  bacteriology  as  a  culture-medium.  It  is  ordinarily  unaffected 
by  the  digestive  fluids,  and  is  not  absorbed  from  the  alimentary 
tract,  hence  is  not  a  food.  But  it  absorbs  water  and  swells, 
thus  serving  the  double  purpose  of  carrying  water  down  into  the 
intestines  and  of  increasing  the  bulk  of  the  colon  contents. 

Its  disadvantages  are:  (i)  It  is  an  excellent  culture-medium 
and  may  favor  the  development  of  intestinal  bacteria,  itself 
becoming  decomposed;  (2)  it  mechanically  retards  the  absorp- 
tion of  food-products ;  and  (3)  by  acting  as  a  demulcent  it  lessens 
the  normal  stimulation  of  the  intestine  by  the  food  material. 
To  overcome  this  last  disadvantage  Schmidt  has  recommended 
the  addition  of  cascara,  and  such  a  preparation  is  on  the  market 
under  the  name  of  regulin.  This  is  slightly  bitterish  from  the 
cascara,  the  amount  of  which  is  not  stated.  A  teaspoonful  to  a 
tablespoonful  may  be  taken  at  night,  or  night  and  morning, 
dry  or  with  water,  or  with  the  morning  cereal.  Its  laxative 
action  is  frequently  delayed  for  several  days;  but  after  that  the 
patient  may  continue  having  a  soft  daily  stool  so  long  as  the 
regulin  is  taken.  Another  laxative  combination  with  agar  is 
ptien olphthale'in-agar,  of  which  one  level  teaspoonful,  weighing 
15  grains  (i  gm.),  contains  |  grain  (0.03  gm.)  of  phenolphthalein. 

Whole  flaxseed  and  psyllium  seeds  are  sometimes  taken  in 
teaspoonful  dose  to  increase  the  bulk  of  the  feces.  Their  muci- 
laginous coat  absorbs  water  and  swells.  They  are  fermentative, 
however,  and  tend  to  produce  gas  and  acid. 

Liquid  Petrolatum. — This  petroleum  oil,  known  also  as  liquid 
vaseline,  liquid  albolene,  Russian  mineral  oil,  and  liquid  paraffin, 
is  not  absorbed  from  the  alimentary  tract  (Bradley,  1911, 


126  PHARMACOLOGY   AND    THERAPEUTICS 

Bloor,  1913),  hence  serves  to  soften  and  to  increase  the  bulk 
of  the  feces.  It  may  exert  an  antiseptic  effect  on  some  of  the 
strains  of  fecal  bacteria,  but  this  has  not  been  demonstrated.  It 
has  little  effect  in  the  stomach,  except  that,  like  other  oils,  it 
tends  to  retard  stomach  emptying  and  gastric  digestion  and 
may  nauseate.  It  is  only  mildly  laxative,  and  frequently  must 
be  given  with  some  stronger  laxative,  such  as  cascara.  A 
disagreeable  effect  in  some  people  is  the  leakage  of  free  oil  from 
the*  anus,  especially  with  the  expulsion  of  flatus.  This  occurs 
with  both  the  light  and  heavy  oils,  and  with  those  of  high  and 
low  viscosity.  The  dose  is  i  ounce  (30  c.c.)  two  or  three  times 
a  day,  the  refined  varieties  being  almost  tasteless  and  readily 
taken.  If  desired,  aromatics  may  be  added.  The  author,  in 
an  investigation  for  the  Council  on  Pharmacy  and  Chemistry 
of  the  American  Medical  Association,  found  that  there  was  no 
difference  in  the  clinical  effects  whether  the  oils  were  of  low  or 
high  specific  gravity  or  of  Russian  or  American  origin,  provided 
that  they  were  properly  refined.  The  Pharmacopoeia  allows  a 
wide  range  of  specific  gravity  and  has  adopted  viscosity  tests 
(see  Part.  I) . 

C.     THE   IRRITANTS 

In  Class  C  we  have  a  large  and  valued  list  of  cathartics,  and 
these  may  be  subdivided  for  convenience  of  study  into  several 
small  groups.  These  are.: 

(a)  Bile  and  bile-salts. 

(&)  The  fixed  oils  and  their  products  (soap  and  glycerin). 

(c)  The  mercurials. 

(d)  The  anthracene  derivatives. 

(e)  Acids,   resins,   and   glucosides   with  drastic  action — the 
drastics. 

(a)    BILE   AND   BILE    SALTS 

(a)  Bile  and  Bile  Salts. — The  bile  salts  are  sodium  glycocholate 
and  sodium  taurocholate.  They  hold  lecithin  and  cholesterol  in 
solution  in  the  bile,  and  serve  as  carriers  of  fats  and  soaps  and  their 
products  into  the  villi  of  the  intestine.  They  are  then  reabsorbed 
by  the  capillaries  and  returned  to  the  liver  by  the  portal  vein. 
Owing  to  their  ready  excretion  by  the  liver  cells  they  act  to 
increase  the  quantity  of  bile.  In  human  bile  from  a  biliary 
fistula  Rosenbloom  found  i.oi  per  cent,  of  total  bile  salts,  and 
Yeo  and  Herroun  found  sodium  taurocholate,  0.055  per  cent., 
and  sodium  glycocholate,  0.165  Per  «.'nt.  In  human  bile  from 
the  gall-bladder  Hoppe-Seyler  found  0.87  per  cent,  of  the  tauro- 
cholate and  3.03  per  cent,  of  the  glycocholate.  Fresh  ox-gall 


THE   FIXED   OILS,    SOAPS,  AND   GLYCERIN  127 

contains  about  3  per  cent,  of  the  salts,  but  is  variable*  in  its 
composition.  The  extract  of  ox-gall  or  dried  ox-gall  and  mixtures 
of  the  salts  are  recommended  in  dose  of  5  grains  (0.3  gm.)  to 
promote  the  production  of  bile,  to  promote  the  splitting  and 
absorption  of  fats,  and  to  enhance  the  action  of  the  anthracene 
cathartics.  They  would  seem  to  be  contraindicated  in  obstructive 
jaundice,  as  in  this  condition  the  system  is  already  overloaded 
with  bile  salts.  In  cases  with  biliary  fistula  Gerster  reported 
that  fresh  bile  through  a  stomach-tube  (it  cannot  be  swallowed) 
was  successful  in  checking  debility.  Inouye  and  Sato  find  that 
8  to  15  grains  (0.5-1  gm.)  of  dried  ox-gall,  taken  one  hour  before 
eating,  promote  the  absorption  of  fat. 

(b)    THE   FIXED   OILS,   SOAPS    AND   GLYCERIN 

1.  Olive  oil  (oleum  olivae)  is  essentially  a  nutritive  and  di- 
gestible fat.     However,  in  amounts  of  one  or  two  tablespoonfuls 
it  may  have  a  mildly  laxative  action,  being  changed  to  soap  and 
glycerin  in  the  intestine.     In  large  amounts,  as  ^  pint  (240  c.c.), 
it  is  only  partly  saponified,  and  gets  some  of  its  laxative  power 
from  increasing  the  bulk  of  the  intestinal  contents.     It  had  at  one 
time  a  reputation  for  the  cure  of  cholelithiasis;  but  as  a  solvent 
for  gall-stones  in  the  gall-bladder  it  has  no  value  whatever.     In 
the  larger  amounts  it  tends  to  form  soap-lumps  which  have  not 
infrequently  been  mistaken  for  gall-stones  in  the  feces.     It  dis- 
tinctly prolongs  the  emptying  time  of  the  stomach. 

Olive  oil  is  also  given  by  mouth  as  a  demulcent  to  diminish 
excessive  hydrochloric  acid  secretion  in  the  stomach,  especially 
in  ulcer,  and  by  rectum  to  allay  irritation,  as  in  proctitis  and 
hemorrhoids.  Warm  oil  is  often  employed  by  rectum  to  soften 
hard  feces,  but  Hertz  found  that  oil  does  not  penetrate  the 
lumps  of  feces,  and  that  these  are  much  more  readily  soft- 
ened by  water. 

2.  Castile  soap  (sapo)  is  nearly  pure  sodium  oleate.     It  is 
mildly  irritant  to  mucous  membranes,  hence  is  laxative.     Soap- 
suds enemata  may  be  made  of  Castile  soap,  or  if  a  stronger  action 
is  desired,  of  laundry  soap,  which  contains  free  alkali  and  is  more 
irritating. 

3.  Glycerin  (glycerinum),  though  slightly  laxative  when  ad- 
ministered by  mouth,  is  chiefly  used  in  the  form  of  the  glycerin 
suppository  (suppositorium  glycerini),  or  as  a  mildly  irritating 
addition  to  an  ordinary  enema.     Hertz  says  it  is  irritant  to  the 
mucous  membrane  of  the  anal  canal,  but  not  to  that  of  the 
rectum. 

4.  Castor  Oil  (Oleum  Ricini). — This  oil  is  saponified  in  the 


128  PHARMACOLOGY  AND   THERAPEUTICS 

small  intestine  to  form  glycerin  and  sodium  ricinoleate,  a  soap 
which  is  much  more  irritant  than  Castile  soap  to  the  intestinal 
mucous  membrane.  Its  great  advantages  are  its  rapidity  of 
action,  its  thoroughness,  its  comparative  freedom  from  irrita- 
tive griping,  and  its  harmlessness  if  catharsis  does  not  result. 
A  dose  of  one-half  to  one  ounce  (15-30  c.c.)  usually  produces  one 
or  more  copious  soft  or  watery  stools  in  from  two  to  six  hours. 
In  some  of  our  cases  over  a  quart  of  stool  was  recovered  afte^r 
one  ounce  of  castor  oil.  It  has  little  if  any  tendency  to  produce 
inflammation,  hence  is  not  a  drastic  cathartic;  but  it  is  a  powerful 
stimulant  of  peristalsis.  This  effect  is  dependent  on  the  forma- 
tion of  the  soap,  for  castor  oil  unsaponified  is  bland  and  non- 
irritant.  If  used  by  rectum,  it  should  be  saponified  with  an 
alkali,  otherwise  it  acts  like  olive  oil.  In  Rowntree's  experi- 
ments, 25  c.c.  by  hypodermatoclysis  had  no  effect  upon  the  bowels, 
and  merely  caused  a  painful  swelling  at  the  site  of  the  injection. 

Administration. — Various  methods  of  administration  have 
been  devised  to  hide  the  nauseating  taste.  The  prepared  oils 
usually  contain  saccharin  and  some  aromatic  such  as  peppermint. 
The  three-layer  or  "sandwich"  method  in  which  the  oil  is  sus- 
pended between  two  layers  of  watery  or  alcoholic  liquid,  is  the 
favorite.  For  this  purpose  compound  tincture  of  cardamom, 
spirit  of  peppermint,  whisky,  orange-juice,  lemon-juice,  lemonade, 
ice-water  or  beer  may  be  employed.  Glycerin  is  sometimes  used 
for  the  lower  layer.  The  layers  should  not  be  stirred  together. 
The  favorite  drug-store  method  is  to  place  some  syrup  of  sar- 
saparilla  in  a  glass  and  then  cause  it  to  foam  by  carbonic  water 
from  the  soda  fountain,  or  by  a  little  tartaric  acid  and  sodium 
bicarbonate.  Then  the  oil  is  poured  in  without  allowing  any 
to  get  on  the  edge  of  the  tumbler.  The  mixture  must  not  be 
stirred.  The  oil  floats  between  some  of  the  syrup  below  and  the 
foam  above,  and  the  whole  is  drunk  without  stopping.  The 
oil  is  not  tasted  at  all.  The  principle  of  these  methods  is  to 
have  the  mouth  and  tongue  wetted  with  a  liquid  (the  top  layer) 
upon  which  the  oil  will  readily  slip  down.  If  any  oil  sticks  to  the 
tongue,  the  taste  will  be  perceived,  though  it  is  stated  that 
vichy-lemonade  following  the  dose  will  prevent  this.  For 
infants  and  children,  an  emulsion  made  with  acacia  and  a 
flavored  syrup  may  be  employed.  There  are  some  powdered 
castor  oils  on  the  market,  such  as  risiccol  and  castor-lax,  made 
by  absorbing  castor  oil  with  magnesia.  To  get  a  full  castor- 
oil  action  they  must  be  taken  in  very  large  dose,  2  ounces  (60 
gm.). 

Therapeutics. — Castor  oil  is  extensively  employed  in  dose  of  i 
ounce  (30  c.c.)  as  an  occasional  brisk  cathartic  for  the  thorough 


Fig.  3. — The  abdomen  of  this  patient  was  greatly  distended  with  gas,  which 
seemed  as  if  in  his  stomach,  though  unrelieved  by  belching.  After  a  rectal  injection 
of  bismuth  this  .v-ray  picture  was  taken,  the  patient  being  in  the  standing  position. 
The  light  areas  in  the  bowel  are  gas.  (Picture  taken  by  Dr.  L.  T.  LeWald.) 


Fit,'-  4.-  The  same  patient  as  in  l"\x.  3.  This  .v-ray  ])icturc  was  taken  after 
free  movements  of  the  bowels  by  castor  oil.  There  was  complete  relief  from 
flatulency.  (Picture  taken  by  Dr.  L.  T.  LeWald.) 


THE   CATHARTIC   MERCURIALS  I2Q 

cleansing  of  the  intestines.  This  may  be  desired  in  fermentative 
diarrhea,  food  or  ptomain-poisoning,  intestinal  flatulency,  or  mu- 
cous colitis,  or  because  of  continued  colonic  stasis.  Such  thorough 
catharsis  is  prone  to  be  followed  by  constipation  for  a  day  or  two 
during  the  refilling  of  the  stagnant  bowel.  Castor  oil  in  cathartic 
amounts  is  not  suited  for  daily  repetition.  By  its  activity  it 
tends  to  congest  and  stimulate  the  female  pelvic  organs,  hence 
must  not  be  employed  as  a  cathartic  during  menstruation  or 
pregnancy,  though  it  is  sometimes  administered  to  bring  on 
labor  pains  at  full  term.  In  colitis  and  intestinal  putrefaction  a 
favorite  treatment  is  a  capsule  containing  2\  minims  (0.15  c.c.) 
of  castor  oil  and  2\  grains  (0.15  gm.)  of  salol,  or  twice  these 
amounts,  three  or  four  times  a  day.  The  effect  of  such  small 
amounts  of  the  oil  is  problematic. 

(c)    THE   CATHARTIC   MERCURIALS 

Calomel  (hydrargyri  chloridum  mite),  the  mild  chloride 
of  mercury,  HgCl,  is  a  bland  or  unirritating  heavy  powder, 
completely  insoluble  in  water.  It  has  few  chemic  affinities, 
but  is  decomposed  by  alkalies.  When  it  is  added  to  a  solution 
of  sodium  carbonate,  it  turns  gray  with  the  formation  of  the 
carbonate,  oxide,  or  hydroxide  of  mercury,  a  change  which 
takes  place,  as  shown  by  Schaefer,  when  the  calomel  passes  from 
the  stomach  into  the  duodenum.  Some  of  the  salt  goes  into 
solution,  for  the  nitrate  contains  mercury  (Schaefer,  MacCallum). 
This  gray  salt  of  mercury  has  more  chemic  affinities  than  calomel, 
is  irritant  locally,  and  is  antiseptic,  and  it  is  upon  this  chemic 
change  that  the  value  of  calomel  in  the  alimentary  tract  largely 
depends.  This  suggests  the  advisability  of  dividing  the  large 
doses,  so  that  not  too  much  is  passed  into  the  duodenum  at  one 
time.  After  cathartic  doses  mercury  is  found  in  the  urine. 

The  result  of  the  irritation  is  increased  peristalsis  beginning 
in  the  duodenum  and  extending  through  the  whole  length  of  the 
bowel.  In  addition,  there  is  a  mild  antiseptic  action,  though 
many  more  bacteria  are  carried  out  by  good  catharsis  than  can 
be  killed  by  an  antiseptic.  Calomel  is  not  a  very  powerful  colon 
stimulant,  so  if  the  dose  is  too  small,  the  movement  may  not  be 
copious;  however,  if  the  dose  is  too  large,  there  may  be  griping, 
rectal  irritation  and  tenesmus,  and  numerous  small  stools. 

At  times,  if  the  action  is  not  severe  enough,  the  bowels  are  not 
thoroughly  cleaned  out,  and  the  result  is  autointoxic  headache 
and  lassitude.  The  explanation  of  this  is  that  the  calomel  hastens 
the  undigested  food  through  the  small  intestine  to  the  colon, 
where  the  putrefactive  bacteria  are  located.  The  raw  proteins, 

9 


130  PHARMACOLOGY  AlSTD   THERAPEUTICS 

not  being  carried  out,  furnish  pabulum  from  which  these  bacteria 
generate  an  extra  amount  of  poisons  of  the  indol  type  (Herter). 
Because  of  this  not  infrequent  sequence  to  calomel,  it  is  the  cus- 
tom to  follow  the  dose  in  about  eight  hours  with  a  saline  cathartic 
to  insure  a  thorough  washing  out  of  the  colon. 

The  calomel  stools  may  be  gray  in  color  from  the  presence  of 
the  mercurous  oxide  or  other  mercurous  salts;  occasionally  they 
are  green  from  the  presence  of  unchanged  biliverdin,  this  being 
due  either  to  the  rapid  carrying  of  the  bile  through  the  intestines, 
or  to  the  prevention  of  .the  usual  reduction  of  the  bile-pigment. 
This  prevention  may  result — (i)  From  the  direct  chemic  action 
of  the  mercury  salt  on  the  pigment;  (2)  from  an  antiseptic  effect 
upon  the  bacteria  which  cause  the  changes  in  bile-pigment,  or 
(3)  from  an  interference  with  the  oxidases.  Frequently  re- 
peated in  large  amounts,  as  in  1<he  Lambert  treatment  for  mor- 
phinism, calomel  results  in  copious  bile  stools,  and  would  seem 
to  have  a  "cholagogue"  action.  But  it  may  be  merely  that  the 
increased  activity  of  the  duodenum  favors  the  outflow  of  stored 
bile  from  the  gall-bladder  and  liver. 

Calomel  may  be  given  in  the  form  of  a  powder  or  tablet 
triturate  (compressed  tablets  and  pills  are  not  recommended, 
as  the  calomel  is  insoluble),  in  amounts  of  1-3  grains  (0.06-0.2 
gm.)  in  divided  doses,  say  f  grain  (0.015  gm.)  every  fifteen 
minutes  for  6  doses.  If  the  stomach  is  irritable,  even  smaller 
amounts  may  be  given  at  a  time.  The  smaller  doses  insure  com- 
plete conversion  of  the  calomel.  A  teaspoonful  has  been  taken 
without  any  violent  effects,  presumably  because  it  passed  through 
the  intestine  mostly  unchanged  (Schaefer) .  It  is  quite  a  common 
practice  to  give  tablets  of  TV  grain  (0.006  gm.)  each  until  i  or  2 
grains  have  been  taken;  but  this  requires  too  many  doses  to  be 
watched,  and  spreads  the  dosage  over  too  long  a  time. 

At  one  time  it  was  taught  that  calomel  should  be  given  with 
sodium  bicarbonate  to  prevent  the  hydrochloric  acid  in  the  stom- 
ach from  changing  it  to  the  poisonous  and  corrosive  bichloride. 
But  it  has  been  shown  that  even  in  highly  acid  gastric  juice  the 
calomel  does  not  change  to  bichloride;  and  it  is  obvious  that  a 
few  grains  of  sodium  bicarbonate  could  have  little  if  any  effect 
in  neutralizing  the  acid  of  the  gastric  juice  during  the  whole 
time  the  calomel  remains  in  the  stomach.  If  the  stomach  needs 
sodium  bicarbonate,  the  patient  may  feel  better  after  such  a  dose, 
but  he  is  not  protected  from  poisoning. 

Diekman,  1899,  mixed  0.5  gm.  of  calomel  with  solutions  of 
ammonium  chloride,  sodium  chloride,  potassium  chloride,  and 
citric  and  tartaric  acids,  and  found  the  loss  through  the  formation 
of  a  soluble  salt  to  be  not  more  than  i  to  3  mg.,  an  amount  that 
if  converted  into  mercuric  chloride  would  not  be  toxic. 


THE    ANTHRACENE   DERIVATIVES  131 

A  very  extensive  research  by  T.  W.  Schaefer,  1910,  establishes 
beyond  doubt  that  there  is  no  bichloride  formed  from  sodium 
chloride,  hydrochloric  acid,  or  hydrochloric  acid  and  pepsin. 
He  found  that  the  administration  of  calomel  to  dogs,  and  sprink- 
ling calomel  on  the  mucous  membrane  of  the  stomach,  intestines 
and  common  bile-duct,  or  mixing  it  with  the  bile  and  pancreatic 
juice  produced  no  bichloride.  When  sprinkled  on  the  duodenal 
mucous  membrane  of  living  dogs  there  was  an  immediate  change 
to  a  gray  color  which  rapidly  darkened,  and  the  ultimate  soluble 
salt  formed  was  found  to  be  mercurous  oxide  (2HgCl+2Na2- 
CO3+H2O  =  Hg2O+2NaCl+2NaHC03).  Sprinkled  lower  down 
in  the  small  intestine  the  change  was  very  slow,  and  in  the  com- 
mon bile-duct  and  in  bile  itself  was  almost  absent. 

Therapeutics. — The  chief  uses  of  calomel  as  a  cathartic  de- 
pend upon  its  combined  cathartic  and  antiseptic  powers.  It  is 
employed : 

1.  At  the  onset  or  during  the  course  of  acute  illnesses. 

2.  In  plethoric  conditions,  such  as  are  usually  associated  with 
habitual  overeating  (so-called  "sluggish  liver"). 

3.  In  intestinal  auto-intoxication,  whether  associated  with 
liver  insufficiency  or  not,  and  in  food  or  ptomain-poisoning. 

4.  In  fermentative  conditions  of  stomach  and  bowels. 

5.  In  hyperacidity  and  "biliousness." 

Each  compound  cathartic  pill  contains  about  one  grain  of 
calomel.  The  other  mercurial  cathartics  are  the  mercury  or 
blue  pill  (massa  hydrargyri),  dose,  5  grains  (0.3  gm.);  and  the 
mercury  with  chalk  (hydrargyrum  cum  creta),  dose,  5  grains 
(0.3  gm.),  in  both  of  which  metallic  mercury  is  in  a  state  of  fine 
subdivision.  The  Pharmacopoeia  requires  that  these  prepara- 
tions shall  not  contain  more  than  traces  of  the  mercury  oxides. 
Metallic  mercury  in  bulk,  when  administered  by  mouth,  may  act 
mechanically,  passing  out  of  the  intestines  unchanged ;  but  poison- 
ing has  occurred  from  its  ingestion. 

Mercurials  used  for  other  purposes  are  occasionally  cathartic, 
e.  g.,  the  protoiodide  given  for  syphilis;  in  such  cases  bismuth  or 
opium  is  sometimes  administered  with  them. 

(d)    THE   ANTHRACENE   DERIVATIVES 

The  drugs  of  this  class  are  the  chemicals,  phenolphthalei'n 
and  other  phthale'ins,  and  the  vegetable  drugs,  aloes,  frangula,  cas- 
cara,  rhubarb,  and  senna.  These  depend  for  their  activity  upon 
resinous  bodies,  known  as  emodins  (trioxymethylanthraquinone), 
and  cathartinic  acid,  or  upon  close  relatives  of  these.  Tschirch 
and  Heppe  report  2.6  per  cent,  of  emodin  in  frangula,  and  0.61 


132  PHARMACOLOGY   AND   THERAPEUTICS 

per  cent,  in  cascara;  but  Stewart  reports  about  1.5  per  cent, 
in  each.  In  rhubarb  there  is  1.5,  in  senna,  i,  and  in  aloes,  0.8 
per  cent.  These  principles  are  rather  readily  absorbed,  so  that 
the  crude  drugs  or  their  galenic  preparations  are  believed  to  be 
more  energetic  as  cathartics  than  the  separated  principles. 
Their  action  tends  to  be  enhanced  by  administration  with  an 
alkali.  In  the  case  of  phenolphthalei'n,  it  has  been  shown  by 
Wood  that  in  the  presence  of  acid  fermenting  intestinal  contents 
there  may  be  no  cathartic  effect.  As  a  rule,  they  do  not  act  so 
well,  or  may  fail  to  act,  in  the  absence  of  bile;  but  usually  in  such 
cases  they  can  be  made  active  by  the  addition  of  soap  or  an  alkali. 

The  essential  action  of  these  drugs  upon  the  bowel  is  that  of  a 
stimulant  to  peristalsis  (Ascher  and  Spiro).  When  they  were 
placed  in  isolated  loops  of  intestine,  Brieger  with  dogs,  and 
Flemming  with  rabbits,  found  no  increase  of  intestinal  secretion 
and  no  evidence  of  inflammation.  Indeed,  when  placed  in  such 
loops  they  tend  to  be  absorbed.  Magnus  found  that  senna  acted 
in  the  large  intestine  only,  and  it  is  highly  probable  that  this  is 
the  case  with  the  other  drugs  of  the  class.  Their  cathartic  effect 
usually  appears  in  from  seven  to  twelve  hours,  the  stools  after 
an  ordinary  dose  being  soft,  but  not  usually  liquid.  When  the 
muscular  action  is  excessive,  cramp  or  griping  results;  and  a  little 
griping  just  preceding  the  time  of  the  stool  is  very  common. 
It  is  claimed  that  resinous  bodies  are  the  cause  of  this,  and  not 
the  cathartic  principles.  Though  these  drugs  are  mildly  irritant, 
even  large  doses  do  not  produce  inflammation  of  the  intestine;  but 
if  they  are  not  carried  out,  the  active  principles,  because  of  their 
absorbability,  pass  from  the  intestine  into  the  blood  and  produce 
systemic  symptoms.  Lieb  found  that  cascara  stimulates  the 
uterus.  One  of  the  author's  patients  took  i  ounce  (30  c.c.)  of 
the  fluidextract  of  cascara,  and,  besides  the  diarrhea,  had  excite- 
ment, hallucinations,  weakness  of  the  legs,  and  a  mild  degree  of 
collapse.  Twenty  hours  later  she  had  completely  recovered. 

Therapeutics. — Beyond  all  other  drugs,  the  anthracene  de- 
rivatives are  preferred  in  habitual  constipation,  especially  that  of 
the  atonic  type.  They  are  not  so  good  in  spastic  constipation. 
By  long  experience  it  has  been  found  that  they  do  not  to  any  great 
extent  lose  their  efficiency  by  repeated  use,  and  in  many  instances 
are  taken  daily,  year  in  and  year  out,  without  even  the  necessity 
of  increasing  the  dose.  It  has  been  noted  further  that  often  a 
small  dose  taken  three  times  a  day  will  be  just  as  efficient  as  a 
much  larger  total  quantity  taken  in  one  dose  at  bedtime.  Rhu- 
barb, frangula,  cascara,  and  senna  contain  tannic  acid.  When 
they  are  used  as  brisk  cathartics,  the  purgation  is  frequently 
succeeded  by  constipation.  This  effect  has  been  attributed  to 


THE    ANTHRACENE    DERIVATIVES  133 

the  large  proportion  of  tannic  acid,  but  is  probably  due  rather 
to  the  thorough  emptying  of  the  bowel,  which  in  chronic  consti- 
pation takes  a  long  time  to  refill.  The  urine  from  rhubarb  is  yel- 
low from  chrysophanic  acid,  which  turns  purple  on  the  addition 
of  alkalies.  The  stools  are  also  yellow.  Aloes,  but  not  aloin,  in 
the  larger  doses  is  especially  prone  to  produce  congestion  of  the  rec- 
tum and  pelvic  organs,  and  consequently  must  be  used  with  caution 
during  menstruation  and  pregnancy  or  if  there  are  hemorrhoids. 
Frangula,  or  buckthorn,  in  addition  to  its  cathartic  principles, 
contains  amygdalin,  similar  to  that  of  bitter  almonds,  and  some 
free  hydrocyanic  acid  (Blyth).  It  is  stronger  and  harsher  than 
cascara,  and  is  employed  chiefly  by  the  veterinarians.  Senna, 
in  the  form  of  a  decoction  (senna  tea),  or  chopped  up  with  figs 
and  prunes,  is  a  favorite  household  remedy.  It  is  prone  to  gripe. 

Preparations  and  Doses. — 1.  Aloes  (Aloe). — Dose,  4  grains 
(0.25  gm.),  tincture  of  aloes,  10  per  cent.;  compound  tincture 
of  benzoin,  2  per  cent.;  pills  of  aloes,  each  2  grains  (0.13  gm.) 
with  soap;  compound  rhubarb  pills,  i^  grains  (o.i  gm.)  in  each; 
compound  extract  of  colocynth,  50  per  cent.,  this  extract  being  used 
in  making  compound  cathartic  pills.  It  is  also  an  ingredient  of 
Warburg's  tincture  (see  Quinine}. 

Aloin  (aloinum),  the  active  principle,  is  a  mixture  of  anthra- 
cene derivatives.  It  varies  somewhat  according  to  the  kind  of 
aloes  from  which  it  is  extracted,  and  is  named  to  correspond. 
For  example,  barbaloin  is  from  Barbados  aloes,  socaloin  from 
Socotrine  aloes,  and  nataloin  from  Natal  aloes.  The  dose  is 
|  grain  (0.015  gm-)-  It  is  frequently  employed  alone  in  pill 
or  tablet  triturate,  and  it  enters  into  the  compound  laxative 
pills  of  the  previous  Pharmacopceia,  better  known  as  Pil.  A.B.S. 
and  I.  Their  formula  is  aloin,  i  grain  (0.013  gm-)>  extract  of 
belladonna,  £  grain  (0.008  gm.);  strychnine,  the  pure  alkaloid, 
T4u  grain  (0.0005  gm.) ;  and  ipecac,  \  grain  (0.004  gm-)  in  each 
pill. 

2.  Frangula  (Rhamnus  frangula),  dose,   15  grains  (i  gm.), 
has  an  official  fluidextract. 

3.  Cascara  sagrada   (Rhamnus  Purshiana),  dose,   15  grains 
(i  gm.) ;  extract,  4  grains  (0.25  gm.) ;  fluidextract,  30  minims  (2  c.c.) ; 
aromatic  fluidextract   (cascara,   glycerin,    25   per  cent.,   licorice, 
magnesia,  saccharin  and  aromatics),  30  minims  (2  c.c.).    Mag- 
nesia is  said  to  lessen  the  bitter  taste.     From  the  author's  ob- 
servations it  seems  to  lessen  the  cathartic  activity.     The  fluid- 
extracts  may  be  given  in  doses  of  10  minims  (0.7  c.c.)  three  times 
a  day,  or  i  dram  (4  c.c.)  at  bedtime,  with  about  equal  effect. 
The  aromatic  fluidextract  was  designed  to  lessen  the  bitter  taste 
and  to  prevent  griping. 


134          PHARMACOLOGY  AND  THERAPEUTICS 

4.  Rhubarb  (rheum),  dose,  15  grains  (i  gm.);  extract,  4  grains 
(0.25  gm.);  fluidextract,  15  minims  (i  c.c.);  tincture,  20  per  cent., 
i  dram  (4  c.c.);  aromatic  tincture  (rhubarb,  20  per  cent.,  with 
cinnamon,  cloves,  and  nutmeg),  \  dram  (2  c.c.);  syrup,  10  per 
cent.,  i  dram  (4  c.c.) ;  aromatic  syrup,  10  per  cent,  of  the  aromatic 
tincture,  2  drams  (8  c.c.);  compound  rhubarb  powder  or  Gregory's 
powder  (rhubarb,  25;  magnesium  oxide,  65;  and  ginger,  10),  dose, 
30  grains   (^  gm.);  compound  rhubarb  pills  (rhubarb,  2  grains 
(0.13  gm.),  and  aloes,  i|  grains  (o.i  gm.),  with  myrrh  and  oil  of 
peppermint),  dose,  2  pills.    The  syrups  are  favorites  for  children. 
Rhubarb  and  soda  mixture   (rhubarb,  1.5;   ipecac,  0.3;   sodium 
bicarbonate,  3.5;  spirit  of  peppermint,  3.5;  glycerin,  35  per  cent., 
and  water),  2  drams  (8  c.c.),  is  no  longer  pharmacopceial. 

5.  Senna    (senna),   dose,    i    dram    (4   gm.);  fluidextract,   \ 
dram  (2  c.c.);  syrup,  20  per  cent.,  2  drams  (8  c.c.);  compound 
syrup  of  sarsaparilla  (senna,  1.5  per  cent.,  with  licorice,  sarsa- 
parilla,  and  aromatics),  4  drams  (15  c.c.);  compound  infusion  or 
black  draught  (senna,  6;  manna  and  magnesium  sulphate,  each, 
12;  and  fennel,  2  per  cent.),  2  ounces  (60  c.c.);  compound  licorice 
powder  (senna,  18;  licorice  root,  23.6;  washed  sulphur,  8;  oil  of 
fennel,  0.4;  and  sugar,  50),  i  dram  (4  gm.).     This  last  is  taken 
stirred  up   with  water.     The  confection  (senna,   10   per  cent.; 
tamarind,  cassia  fistula,  prune,  fig,  sugar,  oil  of  coriander),  i 
dram  (4  gm.),  is  not  now  official. 

Phenolphthalein  (dihydroxyphthalophenone)  is  insoluble  in 
water  and  soluble  in  13  parts  of  alcohol;  dose  .2\  grains 
(0.15  gm.).  It  has  a  mild,  non-griping,  laxative  action,  mostly 
by  stimulating  peristalsis,  but  also  to  some  extent  by  pre- 
venting absorption.  The  effect  is  a  soft,  rather  large  stool. 
In  a  Moreau's  loop  Wood  found  it  unabsorbed  after  two 
hours  and  the  contents  of  the  loop  increased  in  bulk,  but 
he  does  not  say  whether  this  was  due  to  osmosis  or  secretion. 
No  phenol  is  liberated,  and  doses  in  dogs  equivalent  to  from  60 
to  100  grains  in  humans  have  proved  non-toxic  (Wood).  Enor- 
mous doses  intravenously  have  proved  non-toxic  (Abel  and 
Rowntree).  Orland  reports  30  grains  (2  gm.)  taken  by  a  child 
of  3  years  without  ill  effects.  According  to  Rowntree,  it  is 
eliminated  by  the  feces,  and  none  usually  appears  in  the  urine, 
except  after  a  hypodermatic  dose.  But  the  author  has  repeatedly 
found  it  in  the  urine,  an  alkaline  urine  after  small  doses  by  mouth 
being  of  a  pink  color  from  its  presence.  Hydrick,  1914,  reports 
albuminuria  from  one  and  two  grains  (0.06  and  0.12  gm.)  in 
every  case  in  20  tests,  but  in  the  author's  extensive  clinical  use 
of  the  drug  with  frequent  urine  examinations  there  has  been  no 
albuminuria.  In  kidney  disease  a  subcutaneous  dose  of  the  drug 


THE   DRASTICS  135 

is  retarded  in  its  elimination  by  the  urine;  this  is  the  "phthalein 
test"  of  kidney  function.  A  very  mild  and  useful  combination 
is  phenolphthalein-agar,  of  which  a  level  teaspoonful  weighs  about 
15  grains  (i  gm.)  and  contains  \  grain  (0.03  gm.)  of  phenolphtha- 
lem.  It  sometimes  produces  nausea  after  a  few  days'  use. 
Troches  of  phenolphthalei'n  N.  F.  each  contain  1  grain  (0.06  gm.). 

(e)   THE   DRASTICS 

These  are  so  named  because  their  action  is  harsh.  In  over- 
doses they  tend  to  produce  violent  inflammations.  Their  active 
principles  are  chiefly  resinous  glucosides,  such  as  colocynthin  in 
colocynth  and  jalapin  in  jalap,  or  acids,  such  as  cambogic  in 
gamboge  and  crotonic  in  croton  oil. 

Action  and  Uses. — The  drastics  are  strong  local  irritants, 
acting  to  increase  both  peristalsis  and  secretion.  If  one  of  them 
is  placed  in  a  loop  of  intestine  tied  off  without  injury  to  the 
vessels  (a  Moreau's  loop) ,  the  wall  of  the  loop  soon  becomes  con- 
gested and  shows  signs  of  inflammation,  and  the  contents  of  the 
loop  contain  inflammatory  products.  Their  cathartic  action  is 
often  accompanied  by  violent  cramps  and  abdominal  soreness, 
and  in  this  event  may  result  in  stools  containing  blood  or  serum- 
albumin.  After  the  larger  doses  in  man,  if  catharsis  does  not 
result  in  a  reasonable  time,  the  drugs  accumulate  in  the  cecum  and 
colon,  and  may  cause  serious  inflammation.  In  such  case,  too, 
they  may  be  slowly  absorbed  and  passed  out  by  the  kidneys, 
and  these  they  irritate  severely,  even  to  the  production  of  an 
acute  nephritis. 

The  writer  saw  a  case  of  hysteria  which  had  been  treated  for 
obstinate  constipation  by  the  administration,  in  a  period  of 
twenty- four  hours,  of  a  seidlitz  powder,  three  compound  cathartic 
pills,  2  drams  (8  gm.)  of  compound  jalap  powder,  and  3  minims 
(0.2  c.c.)  of  croton  oil.  These  resulted  in  no  movement  of  the 
bowels  until  shortly  after  the  last  dose.  Then  there  was  a 
violent  diarrhea,  with  blood  in  the  stools,  severe  abdominal 
cramps,  bloody  urine,  and  later  suppression  of  urine.  The 
patient  went  into  collapse  and  died  in  twenty-four  hours.  At 
postmortem  examination  there  was  an  intense  inflammation  of  the 
last  few  inches  of  the  ileum  and  the  whole  cecum,  in  which 
region  some  brown  drug  was  visible  clinging  to  the  wall  of  the 
bowel.  There  was  also  an  acute  hemorrhagic  nephritis.  The 
drastics  had  caused  these  lesions. 

On  Dr.  Theodore  Janeway's  service  at  St.  Luke's  Hospital 
a  girl  of  nineteen  was  admitted  with  similar  but  less  severe 
poisoning  from  "bitter  apple"  (colocynth),  given  to  her  by  a 
druggist.  She  had  vomited  six  hours  after  the  dose,  and  re- 


136  PHARMACOLOGY    AND    THERAPEUTICS 

peatedly  for  twenty-four  hours,  with  almost  constant  diarrhea 
and  a  dull  ache  across  the  lower  abdomen.  She  was  admitted 
the  following  day  to  the  hospital,  the  temperature  being  99.8°  F., 
the  pulse  116,  and  the  leukocytes  27,200,  with  82.5  per  cent,  of 
polymorphonuclears.  She  still  had  the  gastro-enteritis,  and 
vomited  twice  after  admission;  but  the  kidneys  were  apparently 
unaffected,  probably  owing  to  the  free  diarrhea.  The  patient 
made  an  uneventful  recovery  in  four  days. 

In  poisoning,  the  immediate  indications  for  treatment  are: 
(i)  To  remove  the  poison  by  a  saline  cathartic  or  castor  oil  or 
by  colon  irrigation,  and  (2)  to  check  collapse.  After  the  immedi- 
ate clearing  out,  bland  oils  or  bismuth  salts  in  large  amounts 
may  be  given.  The  subsequent  treatment  is  that  for  acute 
colitis,  as  by  bland  diet  and  bismuth  salts  by  mouth,  warm  oil 
by  rectum,  etc.  If  the  kidneys  are  affected,  the  treatment  for 
acute  nephritis  is  called  for. 

Therapeutics. — It  will  be  seen  that  these  drugs  are  not  suit- 
able for  daily  administration.  Their  repeated  use  tends  to  pro- 
duce ultimate  constipation  by  accustoming  the  bowel  to  excessive 
stimulation,  and  so  lessening  its  sensitiveness.  Their  employ- 
ment should  be  occasional  only,  and  then  only  when  a  thorough 
cleaning  out  of  stagnating  intestinal  contents  is  desired.  On 
account  of  their  tendency  to  gripe,  which  is  very  great,  they 
should  also  be  given  with  correctives,  such  as  the  extract  of 
belladonna  and  aromatics.  In  a  number  of  instances  a  serious 
drop  in  blood-pressure  has  been  noted  during  their  action. 

Of  the  individuals,  podophyllum,  euonymus,  and  leptandra  are 
rather  mild  and  slow  in  action.  Elaterin  tends  to  produce  such 
copious  watery  stools  that  it  is  a  favorite  in  dropsy.  Crolon 
oil  is  a  fixed  oil  which  contains  as  its  active  principle  crotonic 
acid,  a  substance  so  irritant  that  a  drop  of  the  oil  in  contact 
with  the  skin  for  an  hour  or  two  results  in  the  formation  of  a 
pustule.  A  drop  applied  to  the  tongue  will  sometimes  move  the 
bowels,  even  if  the  patient  is  comatose.  If  the  oil  is  previously 
freed  from  crotonic  acid,  it  has  an  action  similar  to  that  of  castor 
oil  and  a  large  dose -is  necessary  to  move  the  bowels.  But  in 
the  oil  as  we  employ  it  this  action  is  entirely  overshadowed  by 
the  action  of  the  crotonic  acid;  hence  the  drug  as  used  is  not  of 
the  castor  oil  type,  but  is  a  powerful  drastic.  Croton  oil  is 
employed  only  occasionally,  and  then  only  in  rebellious  or  coma- 
tose cases.  It  was  formerly  employed  as  a  pustulant  in  pleurisy, 
pneumonia,  etc.,  but  this  use  of  it  has  been  abandoned.  Its 
dose  is  2  minims  (0.13  c.c.),  and  each  drop  measures  practically 
i  minim  (0.06  c.c.). 

Cautions. — As   the   drastics   are   emmenagogue  and   aborti- 


SALINE    CATHARTICS  137 

facient,  they  must  be  used  with  great  caution,  if  at  all,  during 
menstruation  and  pregnancy.  As  they  are  irritant  and  decidedly 
depressing,  they  should  not  be  employed  in  nephritis,  bowel 
inflammations,  hemorrhoids,  and  low  conditions  of  vitality  or  in 
old  age. 

Preparations  and  Doses. — Elaierin,  ^  grain  (0.006  gm.); 
resin  of  podophyllum,  %  grain  (o.oi  gm.);  colocynth  (bitter  apple), 
i  grain  (0.06  gm.);  croton  oil  (oleum  tiglii),  2  minims  (0.13  c.c.); 
gamboge,  resin  of  jalap,  and  resin  of  scammony,  each,  2  grains 
(0.13  gm.);  podophyllum  and  compound  extract  of  colocynth, 
each,  7^  grains  (0.5  gm.);  jalap,  15  grains  (i  gm.).  Euonymus 
and  leptandra  are  unofficial,  dose,  7^  grains  (0.5  gm.). 

There  are  official,  one  drastic  powder  and  one  drastic  pill, 
viz.,  compound  jalap  powder  (pulvis  jalapae  compositus),  composed 
of  jalap,  35  parts,  and  potassium  bitartrate,  65  parts;  dose,  30 
grains  (2  gm.);  and  compound  cathartic  pills  (pilulae  catharticae 
composite),  containing  calomel  and  compound  extract  of 
colocynth,  each,  i  grain  (0.06  gm.),  resin  of  jalap,  T%  grain 
(0.02  gm.),  and  gamboge,  \  grain  (0.015  gm-)  m  each  pill.  They 
have  not  sufficient  corrective  and  may  gripe  severely.  Dose,  3 
pills.  The  compound  extract  of  colocynth  is  composed  of  purified 
aloes,  50  per  cent.;  extract  of  colocynth,  16  per  cent.;  and  resin 
of  scammony,  14  per  cent.,  with  cardamom  and  Castile  soap. 

Vegetable  cathartic  pills  (pilula?  catharticae  vegetabiles) ,  con- 
taining compound  extract  of  colocynth,  i  grain  (0.06  gm.); 
resin  of  jalap,  T%  grain  (0.02  gm.);  resin  of  podophyllum,  \ 
grain  (0.015  gm.);  extract  of  leptandra,  j  grain  (0.015  gm.); 
extract  of  hyoscyamus,  \  grain  (0.03  gm.),  and  oil  of  peppermint, 
\  minim  (0.008  c.c.),  in  each  pill,  were  official  in  the  U.  S.  P.  1900. 
They  contain  sufficient  corrective,  and  the  griping  is  slight  or 
absent.  Dose,  3  pills. 

Subcutaneous  Purgatives. — A  number  of  active  principles 
will  cause  purgation  when  administered  hypodermatically,  but 
most  of  them,  such  as  aloin,  cascarin,  cathartinic  acid,  colocyn- 
thin,  and  podophyllotoxin  (the  active  principle  of  podophyllin) 
are  too  irritant  locally  for  such  use  in  medicine.  (See  "Cathartics 
Acting  by  Selective  Affinity.") 

D.    SALINE  CATHARTICS 

The  saline  cathartics  are  certain  salts  of  sodium,  potassium, 
and  magnesium.  In  the  study  of  salts  it  has  been  found  that 
their  power  of  penetrating  animal  membranes,  or,  in  the  intes- 
tines, their  absorbability,  depends  on  the  nature  of  the  ions  of 
which  they  are  composed.  Of  ready  absorbability,  the  cations 


138  PHARMACOLOGY  AND  THERAPEUTICS 

(positive  ions)  are  ammonium,  potassium,  sodium,  and  lithium; 
and  the  anions  (negative  ions)  are  chlorides,  bromides,  iodides, 
nitrates,  and  acetates.  Among  those  that  are  absorbed  -with 
difficulty  are  the  cations,  calcium,  magnesium,  cerium,  aluminium, 
and  the  heavy  metals;  and  the  anions,  phosphates,  sulphates, 
tartrates,  citrates,  malates,  and  lactates.  Of  all  these,  mag- 
nesium among  the  basic  ions,  and  citrates,  phosphates,  'sulphates, 
and  tartrates  among  the  acid  ions,  tend  to  give  cathartic  properties 
to  their  compounds.  To  possess  this  property,  the  salt  must 
be  in  solution  in  the  intestines.  (Leathes  and  Starling  have  found 
that  the  pleural  endothelium  absorbed  solutions  of  magnesium 
sulphate  and  sodium  sulphate  just  as  quickly  as  solutions  of 
sodium  chloride,  but  this  is  not  true  of  the  intestinal  wall.) 

Preparations  and  Doses. — 1.  Of  magnesium — the  oxide,  a 
very  light  powder,  and  the  heavy  oxide  (oxidum  ponderosuni) , 
dose,  30  grains  (2  gm.);  the  hydroxide,  in  the  form  of  magma 
magnesia  (milk  of  magnesia),  dose,  2  drams  (6  c.c.);  and  the 
carbonate,  dose,  45  grains  (3  gm.),  are  very  mildly  laxative. 
The  laxative  powers  of  these  insoluble  magnesium  salts  are  pre- 
sumably due  to  the  formation  of  the  soluble  chloride  in  the 
stomach,  or  the  soluble  bicarbonate  in  the  intestine.  In  some 
cases  they  fail  to  dissolve,  and  in  such  have  been  known  to  form 
intestinal  concretions  of  dimensions  large  enough  to  cause  ob- 
struction of  the  bowels.  The  hydroxide  is  the  favorite  for 
children.  The  citrate  (liquor  magnesii  citratis),  dose,  half  to  one 
bottle  of  12  ounces  (360  c.c.),  and  the  sulphate  (Epsom  salt), 
dose,  \  ounce  (15  gm.),  very  soluble  in  water,  are  more  vigorous. 

2.  Of  potassium — the  citrate,  30  grains  (2  gm.);  the  effer- 
vescing citrate,  60  grains  (4  gm.) ;  the  bitartrate  (cream  of  tartar), 
30  grains  (2  gm.) ;  and  the  sulphate,  30  grains  (2  gm.). 

3.  Of  sodium — the  phosphate,  30  grains  (2  gm.);  the  effer- 
vescing phosphate,  2  drams  (8  gm.);  the  sulphate  (Glauber's  salt), 
2  drams  (8  gm.);  and  the  citrate,  30  grains  (2  gm.).     Best  finds 
2  tumblers  of  normal  saline  an  effective  cathartic. 

The  potassium  and  sodium  tartrate,  KNaC4H4O6,  is  Rochelle 
salt,  dose,  2  drams  (8  gm.).  The  seidlitz  powder  is  made  by 
enclosing  tartaric  acid  in  a  white  paper,  and  a  mixture  of  Rochelle 
salt  and  sodium  bicarbonate  in  a  blue  paper.  The  contents  of 
the  papers  should  be  dissolved  separately  in  water,  the  two  solu- 
tions mixed,  and  the  liquid  drunk  as  soon  as  the  violent  efferves- 
cence has  ceased.  It  contains  Rochelle  salt,  2  drams  (8  gm.), 
and  some  acid  sodium  tartrate  formed  during  effervescence. 
Potassium  bitartrate,  KHC4H4O6,  is  soluble  with  difficulty  in 
water,  but  it  forms  Rochelle  salt  in  the  duodenum. 

The  effervescent  preparations  are  usually  preferred,   as  the 


SALINE   CATHARTICS  139 

CO2  present  renders  them  more  palatable  and  less  nauseating. 
They  are  the  solution  of  citrate  of  magnesia,  the  effervescing 
citrate  of  potassium,  the  effervescing  phosphate  of  sodium,  and 
the  seidlitz  powder.  The  laxative  mineral  waters  usually  con- 
tain sodium  sulphate  or  magnesium  salts. 

Pharmacologic  Action. — Skin  and  Mucous  Membranes.— 
Applied  to  the  skin,  solutions  of  these  salts  are  practically  inert, 
as  they  penetrate  the  horny  epithelium  with  difficulty.  Applied 
to  mucous  membranes,  the  concentrated  solutions  are  rather 
irritant  because  of  the  abstraction  of  water. 

Stomach. — Solutions  of  salts  in  fairly  concentrated  form,  as 
they  are  administered  for  cathartic  effects,  have  an  unpleasant 
salt  taste  and  are  irritant  to  the  stomach,  hence  they  tend  to  be 
nauseating.  If  they  lie  in  the  stomach,  they  promote  transuda- 
tion  and  secretion,  and  therefore  their  own  dilution.  The  view 
of  Otto  (1905)  that  solutions  of  salts  are  retained  in  the  stomach 
until  they  become  isotonic  with  the  body  fluids  has  been  in  the 
main  corroborated,  and  Hertz  (1910)  concludes  that  "even  very 
concentrated  solutions  become  almost  isotonic  before  their  evacu- 
ation from  the  stomach."  Brown  (1912)  found  that  hypertonic 
solutions  were  markedly  retarded  in  the  stomach,  and  that  iso- 
tonic and  hypotonic  solutions  leave  less  rapidly  than  the  very 
hypotonic  tap-water.  He  agrees  with  Leven  and  Barrett  that 
from  an  otherwise  empty  stomach  200  c.c.  of  water  leaves  in  about 
twenty  minutes.  In  his  experiments  he  ascertained  that  the 
strong  laxative  mineral  waters  call  forth  considerable  transuda- 
tion  in  the  stomach  and  some  secretion  of  gastric  juice,  and 
strongly  inhibit  the  motor  functions.  They  are  irritant  and  are 
capable  of  inducing  an  acute  gastritis.  In  their  administration, 
they  should  be  properly  diluted  to  bring  them  nearly  to  an  iso- 
tonic condition.  For  example,  Hunyadi  and  Friedrichshall 
should  be  followed  by  an  equal  amount  of  water;  magnesium 
sulphate  should  be  given  in  7.5  per  cent,  solution  (isotonic); 
sodium  sulphate,  in  about  2  per  cent.,  and  Carlsbad  salts  in  about 
3  per  cent.,  solution. 

The  amount  of  fluid  added  by  the  stomach  may  be  quite 
large;  for  instance,  by  a  high  duodenal  fistula  Brown  obtained 
503  c.c.  after  150  c.c.  of  Hunyadi  water,  and  250  c.c.  after  150 
c.c.  of  50  per  cent.  Hunyadi  water  (almost  isotonic).  Cobet 
finds  also  much  fluid  added  in  the  small  intestine. 

Intestines. — Some  years  ago  Hober,  Wallace,  and  Cushny 
administered  solutions  of  various  salts  to  dogs.  On  analysis  of 
the  contents  of  the  intestines  they  found  that  the  salts  which 
were  cathartic  were  regularly  the  ones  not  readily  absorbed, 
and  that  these  acted  as  cathartics  even  when  in  solutions  isotonic 


140  PHARMACOLOGY    AND    THERAPEUTICS 

with  the  blood.  By  means  of  a  cecal  fistula  they  also  measured 
the  fluid  that  reached  the  cecum  after  the  administration  of 
isotonic  solutions.  After  100  c.c.  of  sodium  chloride  solution 
there  was  none  recovered  at  the  cecum  in  one  hour:  it  had  been 
absorbed.  After  100  c.c.  of  sodium  citrate,  75  c.c.  were  recovered, 
and  after  100  c.c.  of  sodium  sulphate,  from  80  to  90  c.c.  were  re- 
covered. They  concluded  that  from  75  to  90  per  cent,  of  ca- 
thartic salts,  with  the  fluid  in  which  they  were  dissolved,  was 
unabsorbed;  and  that  the  catharsis  was  due  to  the  large  bulk  of 
fluid  and  not  to  any  active  stimulation  of  the  intestinal  wall. 
Boas  found  that,  as  the  solution  was  more  concentrated,  it 
proved  less  cathartic  and  more  prone  to  be  absorbed  and  to  pro- 
duce systemic  effects.  He  reports  10  cases  of  magnesium 
poisoning  from  concentrated  doses  of  Epsom  salts.  Meltzer, 
Lucus,  and  Auer  have  pointed  out  that  when  magnesium  sul- 
phate is  administered  intravenously  it  reduces  the  irritability 
of  the  intestines  and  checks  the  peristalsis  aroused  by  physos- 
tigmine  or  barium  chloride.  Magnus  has  shown  that  magnesium 
sulphate  has  no  power  of  itself  to  stimulate  peristalsis,  and  Cohn- 
heim  placed  it  in  the  duodenum,  with  no  effect  on  the  motility 
of  the  bowel.  These  findings  corroborate  the  belief  that  the 
bulk  of  unabsorbed  or  added  fluid  is  the  laxative  agent. 

On  the  other  hand,  a  theory  propounded  by  Aubert  (1852), 
that  the  salts  had  to  be  absorbed  in  order  to  act  on  the  intestine,, 
received  some  corroboration  by  the  work  of  J.  B.  MacCallum 
(1904).  He  found  that  laxative  salines  (sodium  citrate  and 
sulphate)  administered  intravenously  where  cathartic.  This 
has  not  proved,  however,  to  be  regularly  the  case,  and  investi- 
gators have  considered  the  theory  untenable.  However,  Hertz 
(1910),  after  numerous  studies  with  the  #-rays,  has  revived  the 
theory.  He  discovered  that  in  two  patients  with  fistula  at  the 
end  of  the  ileum  the  soluble  purgative  salt  traveled  no  faster 
than  the  heavy  bismuth  salt  given  with  it,  so  he  assumed  that 
it  was  fair  to  judge  by  x-ray  pictures  and  by  auscultation  of  the 
cecal  sounds.  The  x-rays  showed  that  though  a  watery  stool 
was  passed  one  and  a  half  hours  after  the  saline  was  taken,  the 
bismuth  given  with  the  saline  did  not  reach  the  cecum  for  four 
hours.  He  showed  further  that  in  the  watery  stools  from  sodium 
sulphate  there  was  no  increase  in  the  sulphates;  that  half  the 
salt  was  excreted  in  the  urine  in  eight  hours;  and  that  the  greater 
part  of  the  salt  of  the  feces  appeared  the  next  day  after  the 
liquid  stools  had  ceased.  He  concluded  that  the  salt  must  have 
been  absorbed,  that  it  acted  through  the  blood  as  a  stimulant 
both  to  secretion  and  to  peristalsis  of  the  colon,  and  that  it  acted 
independently  of  its  own  appearance  in  the  colon. 


SALINE    CATHARTICS  141 

Sodium  sulphate  administered  intravenously  may  be  slightly 
laxative,  but  magnesium  sulphate  administered  by  mouth  'but 
prevented  from  reaching  the  colon,  or  administered  hypoder- 
matically  or  intravenously  is  not  cathartic;  indeed,  Auer  says  that 
an  intravenous  or  hypodermatic  dose  definitely  checks  peristalsis. 
MacCallum  attributed  the  failure  of  the  intravenous  dose  to  too 
rapid  excretion  by  the  kidneys,  and  believed  that  only  through  the 
intestines  could  a  sufficient  concentration  of  the  salt  be  absorbed 
for  cathartic  effect.  He  suggested  that  these  salts  are  purgative 
by  precipitating  the  calcium  salts  in  the  tissues  and  so  neutraliz- 
ing their  depressing  action.  And,  as  a  matter  of  fact,  the  cathartic 
compounds  are,  for  the  most  part,  the  ones  that  precipitate  cal- 
cium (citrates,  tartrates,  sulphates,  and  magnesium),  and  calcium 
tends  to  inhibit  their  cathartic  action. 

Meltzer's  summing  up  of  the  intestinal  action  of  magnesium 
sulphate  is  as  follows:  The  salt  is  partly  changed  in  the  intestine 
to  sodium  sulphate  and  magnesium  carbonate,  so  that  these  two 
salts  with  some  unchanged  magnesium  sulphate  are  present. 
Since  peristalsis  consists  of  a  coordinated  excitation  (contraction) 
above  and  inhibition  (relaxation)  below,  it  is  promoted  by  an 
increase  of  the  irritability  of  the  excitation  phase  by  the  sodium 
sulphate,  and  an  increase  of  the  irritability  of  the  inhibition 
phase  by  the  unconverted  magnesium  sulphate,  while  at  the 
same  time  the  magnesium  carbonate  attracts  fluid  and  probably 
stimulates  peristalsis. 

It  is  usual  that- in  one  or  two  hours  the  dose  results  in  one  or 
more  watery  stools,  which  consist  of — (i)  the  salt  and  the  water 
in  which  it  is  dissolved;  (2)  some  of  the  gastro-intestinal  contents 
of  which  absorption  is  prevented  by  the  salt;  (3)  some  of  the 
feces  already  formed  in  the  colon;  and  (4)  liquid  added  by 
transudation  and  secretion.  Bayliss  and  Starling,  Magnus, 
Cannon,  and  others  have  shown  that  the  passage  of  liquids  along 
the  intestine  is  different  from  that  of  solid  or  pasty  matter. 
Solids  stimulate  peristalsis,  whereas  liquids  simply  generate 
rhythmic  intestinal  segmentations  (Cohnheim).  The  result  of 
this  is  that,  while  the  liquid  passes  along,  more  or  less  of  the  solid 
contents  of  the  intestine  are  likely  to  be  left  behind.  Hence  a 
saline  cathartic  may  not  be  so  thoroughly  cleansing  as  the  ordi- 
nary more  slowly  acting  stimulants  of  peristalsis. 

In  connection  with  saline  cathartics,  Moreau's  loop  has  be- 
come a  classic  experiment.  It  is  a  loop  of  intestine  tied  off  with- 
out injury  to  the  vessels  and  nerves  of  the  mesentery.  Into  such 
loops  different  salt  solutions  are  injected,  and  they  show  that— 
(i)  An  isotonic  solution  remains  almost  unchanged  at  the  end  of 
three  hours;  (2)  a  hypotonic  solution  loses  in  volume,  that  is, 


142  PHARMACOLOGY  AND  THERAPEUTICS 

is  absorbed,  and  (3)  a  hypertonic  liquid  gains  in  volume.  It  is 
of  interest  that  in  the  latter  case  there  is  no  protein  or  other 
evidence  of  inflammation.  The  gain  in  volume  is  due  either  to 
secretion  or  to  osmosis.  However,  as  the  loops  prevent  peristalsis 
and  segmentation,  the  results  of  such  experiments  are  not  at  all 
conclusive  as  to  the  action  of  saline  cathartics. 

Of  saline  cathartics  as  a  class  it  may  be  said  that — 

1.  They   irritate   the   stomach   and   are   prone    to   produce 
nausea,  an  effect  which  may  be  largely  overcome  by  administer- 
ing them  as  effervescent  drinks. 

2.  Their  stools  contain  much  liquid,  but  no  inflammatory 
products. 

3.  They  are  often  not  thoroughly  cleansing. 

4.  They  act  most  rapidly  and  best  if  taken  fasting,  as  before 
breakfast,  and  with  a  large  volume  of  water.     Their  action  comes 
on  in  an  hour  or  two. 

5.  Their  catharsis  is  the  effect  of  the  increased  bulk  and 
fluidity  of  the  colon  contents,  and  this  is  chiefly  due  to  the  pre- 
vention of  absorption. 

6.  They  do  not  induce  irritant  griping;  but  accompanying 
their  rapid  passage  through  the  intestines  there  may  be  some 
griping,  much  gurgling  of  the  intestines,  and  more  or  less  faint- 
ness  and  nausea. 

7.  If  they  are  not  evacuated,  they  produce  no  inflammation 
and  are  absorbed. 

8.  When  absorbed,  they  pass  out  by  the  kidneys  and  act  as 
diuretics. 

9.  In  moderately  hypertonic  solutions  they  tend  to  remove 
fluid  from  the  body.     This  may  not,  however,  be  the  case  if  the 
dose  is  repeated  daily,  and  especially  if  the  patient  is  on  a  "dry" 
diet,  as  in  dropsy.     In  such  cases  the  salt  may  be  absorbed  and 
only  add  to  the  work  of  the  kidneys. 

10.  Violent  purging  results  in  nausea,  lowered  blood-pressure, 
and  prostration. 

11.  Small  doses  taken  at  night  tend  to  promote  and  soften 
the  morning  stool. 

Therapeutics  of  Salines. — They  may  be  employed: 
i.  In  acute  constipation  or  food-poisoning  as  a  rapidly  act- 
ing non-irritant  cathartic.     2.  In   habitual   constipation  for   a 
short  period  only.    3.  In  intestinal  putrefaction.    4.  After  a  dose 
of  calomel.     5.  As  an  occasional  purge. 

Their  use  in  dropsy  and  obesity  and  to  lessen  the  secretion  of 
milk  in  nursing  mothers  is  dependent  upon  the  power  of  salines 
to  decrease  the  fluid  in  the  body.  For  this  purpose  they  are  ad- 
ministered daily,  a  diet  low  in  liquids  being  prescribed.  But 


RECTAL    TREATMENT  143 

they  usually  very  soon  cease  to  carry  out  excess  of  liquid,  and 
when  profuse  watery  catharsis  does  not  result,  should  be  stopped. 
They  probably  have  no  influence  on  obesity;  at  any  rate,  of 
themselves,  alone  they  are  unable  to  cause  the  body  to  lose  fat. 

Moderate  doses  make  the  stools  soft  and  non-irritant,  so  have 
been  advised  in  hemorrhoids,  fissure  of  the  anus,  etc.;  large 
doses  cause  such  sudden  expulsion  as  to  be  harmful  in  these  con- 
ditions. 

Objections  to  the  habitual  use  of  salines  in  chronic  constipa- 
tion are — (i)  That  they  accustom  the  intestines  to  a  greater  bulk 
of  contents  than  usual  so  that  the  intestines  lose  their  sensitiveness 
to  the  usual  bulk  of  intestinal  contents;  and  (2)  that  they  activate 
the  intestine  for  one  or  two  hours  only,  and  allow  it  to  remain 
"fallow"  for  the  rest  of  the  twenty-four  hours. 

Poisoning  by  Magnesium  Sulphate. — Magnesium  sulphate 
in  very  concentrated  solution  does  not  induce  peristalsis,  is 
absorbed,  and  is  poisonous.  The  toxic  symptoms  are:  marked 
depression  of  respiration  and  a  curare-like  action  on  the  junctions 
of  motor  nerves  with  striated  muscle  (Meltzer  and  his  associates 
and  Barbier).  The  salt  is  eliminated  in  the  urine  and  gives  this 
a  very  high  specific  gravity,  even  1070  or  1080,  which  of  itself 
is  suggestive  of  magnesium  sulphate  poisoning.  The  antidotes 
are  calcium  or  physostigmine  (Meltzer  and  Joseph).  (See 
Magnesium  Sulphate,  under  Anesthetics,  page  313.) 

RECTAL   TREATMENT 

Enemata,  or  rectal  injections,  may  be  for  cathartic,  nutritive, 
or  cleansing  purposes,  or  they  may  be  employed  to  supply  liquid 
to  the  body,  to  cause  the  expulsion  of  gas,  or  to  carry  local  reme- 
dies to  the  mucous  membrane  of  rectum  and  colon. 

The  cathartic  enema  may  be  employed  both  as  a  softening 
agent  for  feces  and  as  an  evacuant.  It  has  the  advantage  of 
affecting  directly  the  rectal  reservoir  and  its  contents. 

(a)  The  softening  agents  are  water,  soapsuds,  olive  oil,  glycerin, 
and  oxgall.  Hertz  found  that  hard  fecal  masses  in  contact  with 
olive  oil  were  not  disintegrated  in  twelve  hours,  while  in  contact 
with  water  they  disintegrated  in  four  hours.  Oxgall,  also,  he 
found  to  have  no  greater  softening  power  than  water.  Glycerin 
increases  the  penetration  of  the  water.  In  cases  of  impacted 
feces  it  has  been  the  custom  to  inject  fresh  oxgall  or  a  i  to  3  per 
cent,  solution  of  extract  of  oxgall  (extractum  fellis  bovis),  or 
warm  olive  oil,  sometimes  with  the  addition  of  castor  oil.  But, 
as  just  stated,  neither  oxgall  nor  olive  oil  is  as  effective  as  water 
in  softening  feces;  and  it  is  a  fact  that  castor  oil  has  little  evacuant 
power  unless  it  is  saponified,  as  in  the  duodenum.  (Inouye  and 


144          PHARMACOLOGY  AND  THERAPEUTICS 

Sato  (1911)  report  that  inspissated  oxgall,  15  grains  (i  gm.)  by 
mouth,  promotes  the  absorption  of  fat.)  For  softening  impacted 
feces,  therefore,  the  best  enemata  are  plain  water,  normal  saline, 
and  soapsuds,  with  the  addition  of  glycerin,  \  ounce  (15  c.c.) 
to  i  pint  (500  c.c.)- 

(b)  The  evacuating  enema  acts  either  by  constituents  capable 
of  irritating  the  rectum  or  by  the  mechanical  stimulus  of  its 
presence  in  the  rectum.  It  consists  usually  of  from  one  pint  to 
two  quarts  of  warm  soapsuds,  or  soapsuds  with  the  addition  of 
glycerin,  \  ounce  (15  c.c.),  or  oil  of  turpentine,  \  ounce  (15  c.c.). 

In  tlie  cat,  Cannon  has  observed  peristalsis  of  the  small  in- 
testine as  the  result  of  a  rectal  injection  and  antiperistalsis  of  the 
colon.  In  tests  with  bland  nutritive  enemata  of  milk,  eggs, 
starch,  and  bismuth  subnitrate  he  found  that  in  every  instance 
antiperistaltic  waves  carried  the  material  to  the  cecum.  Small 
enemata  never  passed  the  ileocecal  valve,  but  large  enemata  of 
about  the  capacity  of  the  large  intestine  would  often  pass  into 
the  small  intestine. 

In  man,  if  a  quantity  of  liquid  is  introduced  three  or  four 
inches  into  the  rectum,  the  patient  being  in  the  knee-elbow 
position  or  on  the  back,  it  will  not  infrequently  reach  the  cecum; 
but  this  happens,  as  a  rule,  only  when  the  liquid  is  bland  and  is 
administered  slowly,  so  as  not  to  start  the  defecation  reflexes.  In 
some  cases,  however,  even  an  irritant  enema  passes  quickly  to 
the  cecum,  and  in  rare  instances  has  been  vomited.  In  these 
cases,  of  course,  the  enema  fails  to  act  as  an  immediate  evacuant. 

The  evacuant  enema  is  given  rapidly,  and  by  a  sudden  dis- 
tention  of  the  rectum  or  by  direct  irritation  of  the  bowel  wall 
results  reflexly  in  active  forward  peristalsis,  at  least  of  the  de- 
scending colon,  with  expulsive  contraction  of  the  rectum  and 
relaxation  of  the  anal  sphincter. 

In  the  treatment  of  chronic  constipation  enemata  should  not 
be  given  over  too  long  periods,  for  they  accustom  the  bowel  to  the 
stimulus  of  a  bulk  of  material  greater  than  that  of  the  normal 
feces. 

Enemata  to  induce  the  expulsion  of  gas  may  be  of  soapsuds 
made  from  yellow  laundry  soap;  of  soapsuds  and  turpentine, 
^  ounce  (15  c.c.);  of  turpentine,  \  ounce  (15  c.c.),  with  olive 
oil,  6  ounces  (180  c.c.);  of  ice  water;  of  infusion  of  chamomile;  or 
of  tincture  of  asafetida,  4  drams  (15  c.c.),  or  spirit  of  peppermint, 
i  dram  (4  c.c.),  added  to  a  pint  of  hot  water.  They  are  employed 
in  the  tympanites  of  typhoid  fever,  pneumonia,  post-operative 
intestinal  paralysis,  etc. 

Nutritive  enemata  are  employed  for  feeding  when  it  is  neces- 
sary to  spare  the  stomach.  They  must  be  small  in  bulk,  i.  e., 


RECTAL   TREATMENT  145 

about  6  or  8  ounces  (180-240  c.c.),  warmed,  and  slowly  adminis- 
tered so  that  they  will  not  be  expelled.  They  may  be  given  at 
six-  or  eight-hour  intervals,  and  their  administration  should  be 
accompanied  by  a  daily  cleansing  enema  of  normal  saline  or 
weak  soapsuds.  The  ingredients  of  the  enema  should  be  made 
as  absorbable  as  possible.  The  available  foods  are  dextrose, 
sugar,  sugar  of  milk,  fully  peptonized  milk,  whisky,  brandy,  and 
raw  eggs.  The  white  of  egg  peptonized  with  the  milk  may  be 
absorbed,  but  the  ingredients  of  the  yolk  may  not  be.  Dextrose 
solutions  are  absorbable,  but  in  strengths  above  5  or  6  per  cent, 
irritate  and  cause  evacuation.  Whether  the  other  sugars  are 
inverted  and  absorbed  is  a  question.  Magnus  says  that  cane- 
sugar  is  absorbable.  The  absorption  of  oils  is  promoted  by 
emulsification  with  3  to  5  per  cent,  of  lecithin  (Congdon),  and 
this  may  apply  to  egg-yolk.  It  is  possible  that  the  amino-acids, 
such  as  tyrosin,  histidin,  and  arginin,  may  prove  useful  for  rectal 
feeding,  as  they  represent  the  end-products  of  protein  digestion. 
Short  and  Bywaters  found  a  decided  increase  in  the  urinary 
nitrogen  from  the  administration  of  amino-acids  by  rectum. 
They  recommend  milk  pancreatinized  twenty-four  hours,  with 
the  addition  of  5  per  cent,  of  glucose. 

Colon  or  rectal  irrigations  of  saline  solution  slowly  admin- 
istered, using  both  inlet  and  outlet  tubes,  are  frequently  employed 
to  clean  out  mucus  or  the  products  of  intestinal  putrefaction,  to 
activate  the  kidneys,  or  to  supply  fluid  after  hemorrhage.  The 
inlet  tube  may  be  inserted  6  or  8  inches,  and  the  outlet  tube  about 
half  as  far.  The  "continuous  drip"  irrigation,  in  which  a  flow  of 
warm  saline  20  to  60  drops  per  minute,  is  kept  up  continuously, 
day  and  night,  was  recommended  by  Murphy  for  postoperative 
tympanites  and  shock.  Potassium  acetate  or  sodium  bicarbonate 
may  be  substituted  for  the  sodium  chloride. 

The  rectum  is  a  favorite  channel  for  the  administration  of 
warm  normal  saline  solution  to  supply  liquid  to  the  body  after 
severe  hemorrhage. 

Rectal  suppositories  may  be  of  wheat-gluten,  soap,  glycerin, 
or  plain  or  medicated  cocoa-butter.  The  evacuant  ones  act 
largely  as  a  foreign  body,  mechanically  stimulating  the  rectum 
to  expel  it.  Even  a  stick  of  ice  or  an  undisintegrated  stick  of 
soap  will  often  have  the  same  effect.  Glycerin  suppositories, 
made  of  almost  pure  glycerin,  with  a  little  sodium  stearate  to  give 
a  solid  consistence,  are  much  employed.  The  glycerin  acts  as 
an  irritant  in  the  anal  canal,  but  not  in  the  rectum  (Hertz). 
Suppositories  are  especially  useful  where  the  feces  come  down 
to  the  rectum,  but  are  retarded  in  their  expulsion  by  a  tight  or 
sensitive  sphincter. 


146          PHARMACOLOGY  AND  THERAPEUTICS 

ANTI-DIARRHEICS 

Diarrhea  has  so  many  causes  that  remedies  of  entirely  dif- 
ferent action  may  be  required  in  the  different  types.  In  fer- 
mentative diarrhea  castor  oil  may  be  indicated,  followed  by  a 
bland  protective  like  bismuth  subnitrate.  In  severe  diarrhea 
camphor,  lead  acetate,  or  opium  may  be  the  needed  remedy. 
The  anti-diarrheics  are :  bismuth  salts  (subnitrate,  subcarbonate, 
and  subgallate),  cerium  oxalate,  calcium  carbonate  (chalk), 
camphor,  lead  acetate,  opium,  the  vegetable  astringents,  and 
castor  oil.  They  are  all  studied  in  detail  elsewhere.  The  Sun 
Cholera  Mixture,  N.  F.,  contains  in  each  teaspoonful  6  minims 
(0.4  c.c.)  each  of  the  tinctures  of  capsicum  and  rhubarb,  and  12 
minims  (0.8  c.c.)  each  of  the  spirit  of  camphor,  spirit  of  pepper- 
mint, tincture  of  opium  and  alcohol.  Dose,  f  dram  (2  c.c.). 
SquiWs  Diarrliea  Remedy,  N.  F.,  is  made  of  tincture  of  opium  and 
spirit  of  camphor,  each,  7  minims  (o.  5  c.c.),  tincture  of  capsicum, 
4  minims  (0.25  c.c.),  chloroform,  5  minims  (0.3  c.c.),  and  alcohol 
enough  to  make  i  dram  (4  c.c.).  Dose,  \  dram  (2  c.c.).  Pills 
of  lead  acetate,  2  grains  (0.13  gm.),  and  powdered  opium,  i 
grain  (0.06  gm.),  are  also  employed.  A  favorite  type  of  pre- 
scription in  simple  diarrhea  is:  bismuth  subnitrate,  3  drams 
(12  gm.),  camphorated  tincture  of  opium,  ^  ounce  (15  c.c.), 
and  sufficient  chalk  mixture  to  make  2  ounces  (60  c.c.).  Dose, 
a  dessertspoonful  every  two  or  three  hours,  or  after  each  move- 
ment of  the  bowels. 

MINERAL  WATERS 

A  mineral  water  is  a  natural  water  containing  one  or  more 
ingredients  different  from,  or  in  greater  quantity  than,  those  in 
ordinary  drinking  or  washing  water.  Many  bottled  waters  are 
not  mineral  waters.  As  obtained  from  the  earth,  they  are 
thermal  when  they  are  distinctly  warmer  than  the  average  sur- 
rounding temperature,  otherwise  non-thermal;  some  writers  adopt 
70°  F.  as  the  dividing  line  between  these.  Warm  waters  are  those 
from  70°  to  98.6°  F. ;  hot  waters  are  those  above  98.6°  F.  They 
may  be  sparkling  or  effervescent,  i.  e.,  impregnated  with  carbon 
dioxide,  or  still,  i.  e.,  non-effervescent.  They  may  be  sulphurated, 
containing  hydrogen  sulphide  gas.  Their  mineral  constituents 
are  sodium,  potassium,  lithium,  magnesium,  calcium,  iron, 
aluminium,  and  arsenic,  in  the  form  of  sulphates,  nitrates, 
chlorides,  bromides,  iodides,  borates,  and  silicates.  In  a  number 
of  the  waters  the  percentage  of  the  ingredients  has  been  found 
quite  variable  at  different  seasons  and  in  different  years.  The 
report  of  Hay  wood  and  Smith  (1905),  of  the  United  States 


MINERAL    WATERS  147 

Bureau  of  Chemistry,  on  the  "Mineral  Waters  of  the  United 
States,"  and  that  of  Francina,  on  "European  Waters,"  furnish 
valuable  data. 

A  medicinal  classification  is  not  readily  made  because  many 
waters  contain  more  than  one  ingredient  of  importance.  All  are 
either — (i)  Alkaline,  i.  e.,  having  an  alkaline  reaction;  this 
comes  from  carbonates  and  bicarbonates,  or  in  a  few  instances 
from  borates  and  silicates.  (2)  Saline,  containing  chlorides, 
nitrates,  or  sulphates  in  excess.  (3)  Alkaline  saline,  combining 
the  properties  of  the  alkaline  and  the  saline,  or  (4)  Acid,  in  which 
there  is  free  sulphuric  or  hydrochloric  acid. 

Any  of  these  may  contain  one  or  other  of  the  special  elements, 
and  are  known  as : 

Sulphur  waters — those  containing  sulphuretted  hydrogen  and 
other  sulphides.  They  are  usually  from  "red"  or  "white" 
sulphur  springs,  these  names  being  obtained  from  the  precipita- 
tion of  sulphur.  The  red  sulphur  gets  its  color  from  iron.  Ex- 
amples are  the  waters  of  Richfield  Springs  or  Sharon  Springs. 

Chalybeate  or  ferruginous  waters — those  which  contain  iron, 
usually  in  the  form  of  the  sulphate  or  bicarbonate,  as  Spa  or 
Sweet  Chalybeate. 

Arsenical  waters — those  which  contain  arsenic,  as  Levico 
and  Bourboule. 

Alum  waters — those  which  contain  aluminium  salts.  Rock- 
bridge  alum  water  contains  337  grains  of  aluminium  sulphate 
per  million  and  is  astringent. 

Bromine  waters,  iodine  waters,  etc. 

Lithia  waters — of  these,  Haywood  and  Crook  say  "lithium 
seldom  or  never  occurs  in  waters  in  large  enough  quantities  to  be 
a  predominating  basic  constituent."  In  their  analyses,  Buffalo 
and  Londonderry  Lithia  Waters  show  only  a  trace.  Otterburn 
Lithia,  0.03  part,  Geneva  Lithia,  o.i  part,  and  White  Rock 
Lithia,  12.6  parts  of  lithium  per  million.  Thus  the  term  "lithia 
water"  is  a  misnomer. 

Examples  of  alkaline  waters  are  Vichy,  Apollinaris,  Seltzer, 
Bear  Lithia,  Great  Bear,  Manitou.  Of  alkaline  saline  are  the 
Saratoga  waters  (Carlsbad,  Congress,  Hathorn,  High  Rock, 
Vichy,  Seltzer)  and  White  Rock  Lithia.  The  Saratoga  waters 
are  much  poorer  in  salts  now  than  formerly.  The  saline  waters 
are  those  containing  abundance  of  salts  and  not  alkaline,  such 
as  Pluto  and  Mount  Clemens. 

From  a  medicinal  point  of  view  the  purgative  waters  are  the 
most  important.  In  nearly  all  cases  they  owe  their  cathartic 
action  to  sodium  sulphate  (Glauber's  salt),  magnesium  sulphate 
(Epsom  salt),  magnesium  chloride,  or  magnesium  bicarbonate. 


148  PHARMACOLOGY    AND    THERAPEUTICS 

The  waters  which  contain  a  large  percentage  of  magnesium  salts 
are  bitter.  Those  whose  action  is  due  to  sodium  sulphate  alone 
are  the  Carlsbad  waters  and  Marienbad,  which  are  alkaline,  and 
Villacabras,  which  is  neutral.  The  published  analyses  of  the  Carls- 
bad waters  differ  considerably  from  one  another.  Those  owing 
their  action  to  both  sodium  sulphate  and  the  magnesium  salts 
are:  Pluto,  Friedrichshall,  Carabana,  Rubinat  Condal,  and  the 
Hungarian  waters,  Apenta,  Franz  Josef,  and  Hunyadi  Ja"nos. 
"Pluto  concentrated"  is  artificial  and  does  not  have  its  salts  in 
the  same  relative  proportions  as  Pluto  water.  It  contains  about 
65  grains  (4.3  gm.)  of  sodium  sulphate  and  30  grains  (2  gm.)  of 
magnesium  sulphate,  in  a  dose  of  2  ounces  (60  c.c.).  Mount 
Clemens  water  is  essentially  a  solution  of  magnesium  chloride. 

Mineral  waters  may  be  used  for  the  bath  or  internally.  At 
the  various  "springs,"  both  the  baths  and  the  drinking  of  the 
waters  are  considered  requisite  parts  of  the  treatment.  It  is 
claimed  that  some  of  the  waters  contain  radium  emanations  and 
are,  therefore,  more  effective  when  taken  fresh.  The  value  of  a 
"cure"  taken  at  one  of  the  mineral  spring  resorts  depends  less 
on  the  character  of  the  water  than  on  the  regulation  of  rest, 
exercise  and  food,  the  regular  taking  of  the  baths,  and  the 
influence  of  freedom  from  home  or  business  cares  amid  pleasant 
surroundings. 

REMEDIES  WHOSE  CHIEF  ACTION  IS  UPON  THE  CIR- 
CULATION 

(a)  General  circulatory  stimulants. 

(b)  Measures  to  increase  the  volume  of  the  blood. 

(c)  Cardiac  depressants. 

(d)  Arterial  dilators. 

(e)  Measures  to  lessen  the  volume  of  the  blood. 

THE   PHYSIOLOGY   OF   THE    CIRCULATION 

The  following  is  a  brief  review  from  a  pharmacologic  stand- 
point: 

The  circulatory  organs  are  for  the  purpose  of  carrying 
certain  materials  to  and  from  the  tissues  by  means  of  the  blood ; 
and  since  all  exchanges  between  the  blood  and  the  tissues  are 
made  through  the  capillary  walls,  it  may  be  said  that  the  function 
of  the  circulatory  organs  is  to  maintain  an  adequate  capillary 
blood-flow.  Hence  the  circulatory  organs  need  treatment  when 
they  fail  to  maintain  an  adequate  capillary  blood-flow.  This 
capillary  blood-flow  is  dependent  somewhat  upon  the  viscosity 
of  the  blood,  but  mainly  upon  the  relation  between  the  general 


THE    PHYSIOLOGY    OF    THE    CIRCULATION  149 

arterial  blood-pressure  (the  driving  force)  and  the  caliber  of  the 
arterioles  which  lead  to  the  capillaries  (the  peripheral  resistance). 
These  arterioles,  being  actively  contractile,  serve  as  adjustable 
gates  by  means  of  which  the  amount  of  blood  passing  to  any  given 
set  of  capillaries  may  be  regulated.  And  it  is  obvious  that  if  the 
general  arterial  pressure  remains  the  same  an  increase  in  the 
caliber  of  any  given  set  of  arterioles  will  result  in  a  greater 
supply  of  blood  to  the  capillaries  of  that  set ;  and  that  if  the  caliber 
of  these  arterioles  remains  the  same,  an  increase  in  the  general 
arterial  pressure  will  have  a  similar  result.  The  adjustment 
of  the  caliber  of  individual  sets  of  arterioles  without  produc- 
ing the  same  changes  in  other  sets  is,  for  the  most  part,  im- 
possible therapeutically;  but  the  caliber  of  the  arterioles  as  a 
class  may  be  readily  changed  by  remedial  measures. 

Capillary  flow  may  be  altered  by  changes  in — (i)  The  total 
amount  of  blood  in  the  arterial  system;  (2)  the  heart's  output 
in  a  given  time;  (3)  the  general  peripheral  or  arteriole  resistance, 
and  (4)  the  viscosity  of  the  blood. 

The  amount  of  blood  in  the  arteries  may  be  decreased  by  its 
accumulation  in  the  veins,  by  its  loss  from  the  body  (as  in  hemor- 
rhage or  blood-letting) ,  or  by  the  excessive  removal  of  other  fluid 
from  the  body,  as  in  cholera  or  other  severe  diarrheal  conditions. 
It  may  be  increased,  especially  after  a  preliminary  loss,  as  in  hem- 
orrhage or  cholera,  by  increased  receipt  from  the  veins  or  tissues, 
by  transfusion  of  blood,  by  intravenous  administration  of  saline 
solutions,  and  by  rapid  absorption  of  liquid,  e.  g.,  saline  solutions, 
from  the  alimentary  tract  or  elsewhere.  The  heart's  output  may 
be  affected  by  measures  which  influence  either  the  filling,  the 
capacity,  the  rate,  or  the  strength  of  the  ventricles.  The 
peripheral  resistance  may  be  altered  by  measures  which  change 
the  caliber  of  the  arterioles. 

It  will  be  obvious  that  the  rate  of  capillary  flow  is  not  to  be 
judged  by  the  degree  of  general  arterial  pressure.  For  example, 
suppose  the  heart  increases  its  output,  but  the  arterioles  dilate 
just  enough  to  let  the  additional  blood  through.  Then,  though 
the  general  pressure  remains  unchanged,  yet  more  blood  flows 
through  the  capillaries  and  the  circulation  is  more  active.  As  a 
matter  of  fact,  it  has  been  found  in  man  that  the  mechanisms 
which  control  blood-pressure  are  so  neatly  adjusted  that  it  is 
well-nigh  impossible  to  cause  a  decided  rise  in  arterial  pressure  by 
a  therapeutic  dose  of  any  slowly  acting  drug,  and  yet  some  such 
drugs,  e.  g.,  digitalis,  do  have  great  power  to  improve  the  circula- 
tion. So  the  therapeutic  value  of  a  circulatory  drug  cannot  be 
measured  by  its  ability  lo  raise  arterial  pressure  in  man.  However, 
in  dogs  and  other  laboratory  animals  we  can  inject  toxic  doses 


150  PHARMACOLOGY    AND    THERAPEUTICS 

intravenously,  and  thus  bring  about  a  concentration  of  the  drug 
in  the  blood  which  will  produce  effects  of  sufficient  degree  and 
with  sufficient  rapidity  to  submerge  the  dissipating  influences. 
And  these  give  us  valuable  information  as  to  the  real  sites  and 
modes  of  action  of  a  drug. 

The  Heart. — The  activities  of  the  heart  depend  upon  a  num- 
ber of  things,  viz.,  the  strength  of  contraction  (contractility), 
the  tone  of  the  muscle,  the  recuperative  power,  the  irritability, 
the  conductivity  of  the  stimulus  from  the  pacemaker  to  the  vari- 
ous chambers  of  the  heart,  or  from  one  chamber  to  another,  the 
rate  of  stimulus  production,  the  rate  of  the  beat,  and  the  rhythm. 

The  heart's  action  may  be  affected  by  remedies  directly  or 
indirectly. 

1.  Directly,  by  action  upon  its  muscle  substance.     If  the 
muscle  is  stimulated,  there  is  an  increase  in  its  tone,  in  its  strength 
of  contraction,  and  in  its  irritability;  if  the  muscle  is  depressed, 
there  are  the  opposite  effects. 

2.  Indirectly,  either  through  its  nervous  elements,  through 
changes  in  its  coronary  circulation,  or  through  changes  in  the 
peripheral  resistance. 

The  nervous  elements  of  pharmacologic  importance  are  the 
accelerator  and  the  vagus  systems.  The  accelerators  belong  to 
the  sympathetic  nervous  system.  The  center  is  presumed  to 
have  its  seat  somewhere  in  the  brain,  though  it  has  not  yet  been 
clearly  located.  The  fibers  from  this  terminate  about  certain 
cells  in  the  anterior  horns  of  the  upper  portion  of  the  spinal  cord. 
These  neurons  in  turn  connect  with  the  sympathetic  ganglia,  and 
the  cells  of  these  send  fibers  to  terminate  in  the  heart  wall  at 
the  sinus  node.  The  accelerator  system,  therefore,  is  composed 
of  centers,  nerves,  ganglia,  and  nerve-endings.  The  effects  of 
accelerator  stimulation  are  those  of  direct  muscular  stimulation, 
as  a  rule.  Rothberger  and  Winterberg  (1910)  have  shown  that 
stimulation  of  the  left  accelerator  results  in  overaction  of  the 
left  ventricle,  and  stimulation  of  the  right  accelerator  in  over- 
action  of  the  right  ventricle.  But  accelerator  influence  is  not 
always  certain,  and  at  times  accelerator  stimulation  will  result 
merely  in  an  increase  in  contractility  without  change  of  rate, 
or  an  increase  of  rate  without  change  in  contractility  (Howell). 
The  increase  of  rate  is  the  result  of  shortened  diastole. 

The  vagus  system  begins  at  the  vagus  center,  a  collection  of 
cells  on  either  side  of  the  middle  line  in  the  medulla  oblongata, 
and  from  here  the  nerve-fibers  pass  as  the  vagus  nerves  to  groups 
of  cells  in  the  heart  wall  known  as  vagus  ganglia.  From  the  cells 
of  these  ganglia  fibrils  pass  to  the  sinus  node  (the  normal  pace- 
maker) in  the  auricle,  and  to  the  auriculo ventricular  junctional 


THE   PHYSIOLOGY   OF    THE    CIRCULATION  151 

tissues  at  the  bundle  of  His.  The  vagus  system  comprises,  there- 
fore, the  vagus  centers,  vagus  nerves,  vagus  ganglia,  and  vagus 
nerve-endings.  Its  chief  function,  so  far  as  the  heart  is  con- 
cerned, is  that  of  restraint  or  inhibition,  and  it  is  called  the 
cardio-inhibitory  nerve.  Stimulation  of  any  part  of  the  vagus 
system  results  in  slowing  and  weakening  of  the  heart-beat,  with 
depression  of  conductivity  and  loss  of  tone;  while  depression  of 
the  vagus  system  sets  free  the  heart  and  results  in  increased 
frequency  and  strength  of  the  beat  and  increased  tone.  The 
loss  of  tone  is  manifested  by  greater  relaxation  in  diastole;  the 
diminished  contractility  by  less  complete  contraction  in  systole. 
The  slowing  occurs  essentially  through  a  longer  diastolic  pause. 
Vagus  stimulation  and  depression  are  very  definite  in  their 
effects,  and  so  great  is  the  inhibitory  action  of  the  vagus  that, 
under  powerful  stimulation,  it  can  momentarily  bring  the  heart  to 
a  complete  standstill  in  a  state  of  diastolic  relaxation.  Or  excess- 
ive vagus  action  may  have  the  effect  of  partially  or  completely 
checking  the  conduction  of  impulses  from  the  auricle  to  the 
ventricle,  with  the  production  of  heart-block.  The  vagus  action 
is  primarily  on  the  auricle,  and,  so  far  as  knowrn,  is  exerted  upon 
the  ventricle  only  through  the  auriculoventricular  bundle,  except, 
perhaps,  in  a  few  cases  in  which  the  fibers  of  the  right  vagus  pass 
directly  to  the  ventricle  (Cohn). 

Robinson  and  Draper  (1912),  in  electrocardiogram  studies 
made  during  pressure  of  the  human  vagus  in  the  neck,  found  that 
while  pressure  on  either  vagus  slows  the  rate  of  contraction  and 
retards  conduction  from  auricle  to  ventricle,  yet  pressure  on  the 
right  vagus  has  its  predominating  effect  on  the  rate  of  the  whole 
heart,  while  pressure  on  the  left  vagus  predominates  in  inter- 
ference with  auriculoventricular  conduction. 

The  vagi  and  accelerators  are  thus  in  some  ways  antagonistic, 
and  as  both  are  in  a  state  of  constant  activity,  they  form  a  sensi- 
tive balanced  control-mechanism  which  favors  prompt  response 
to  any  influence.  (Compare  with  the  antagonistic  elements 
governing  the  size  of  the  pupil.)  The  vagus  and  accelerator 
systems  may  be  stimulated  or  depressed  directly  in  any  part  of 
the  system;  or  rejiexly,  through  the  center,  by  afferent  impulses 
coming  from  other  parts  of  the  body. 

Resistance. — Up  to  its  limit  of  power,  a  heart  will  beat  more 
slowly  and  more  strongly  in  response  to  increased  peripheral 
resistance;  but  if  the  resistance  is  beyond  the  cardiac  power, 
the  result  is  weakness  and  dilatation  and  cardiac  failure. 

Coronary  Circulation. — Other  things  being  equal,  slowing  of 
the  heart  means  improved  supply  of  coronary  blood,  resulting 
in  better  nutrition  and  better  recuperative  power.  It  has  been 


152          PHARMACOLOGY  AND  THERAPEUTICS 

demonstrated  by  Stewart  and  Pike  (1910)  that  the  heart  will  not 
continue  beating  unless  there  is  a  certain  intracoronary  pressure. 

The  time  of  filling  of  the  heart,  i  e.,  the  diastole  proper,  de- 
pends upon  the  venous  pressure,  and  is  usually  not  much  greater 
than  the  time  of  systole.  The  remainder  of  the  diastolic  pause, 
i.  e.,  the  diastasis,  is  the  period  during  which  food  and  oxygen 
reach  the  heart  through  the  coronary  arteries  and  during  which 
the  heart  recuperates.  If  the  period  of  diastasis  is  shortened, 
the  heart  beats  more  frequently,  and  its  output  per  minute  is 
increased.  But  if  the  shortening  of  the  diastasis  is  too  great, 
or  if  there  is  no  diastasis,  the  heart  soon  fails  for  lack  of  a  period 
of  nutrition  and  rest.  The  maximum  output  occurs  when  the 
period  of  diastasis  is  just  abolished,  but  under  such  conditions 
the  heart  cannot  long  maintain  its  efficiency.  On  the  other  hand, 
if  the  period  of  diastasis  is  too  prolonged,  the  heart  beats  so 
few  times  in  a  minute  that  it  cannot  maintain  adequate  arte- 
rial pressure.  Thus  it  is  evident  that  failure  of  the  circulation 
may  result  from  too  few  beats  per  minute  or  from  too  many 
beats.  And  it  may  be  assumed  that  for  each  heart  there  is  an 
optimum  rate,  which  is  the  rate  that  gives  the  greatest  number  of 
beats  consistent  with  a  proper  resting  period.  This  optimum 
rate  is  neither  the  maximum  rate  nor  that  which  allows  the  great- 
est output  of  blood;  so  that  the  effect  on  the  rate  of  the  heart  is 
not  the  criterion  of  efficiency  for  a  circulatory  drug. 

Regardless  of  which  control  mechanism  is  utilized,  the  heart's 
action  can  practically  be  modified  as  regards  its  rhythm,  its 
rate,  its  contractility,  its  tone,  its  irritability,  and  its  conductivity. 
The  rhythm  is  either  regular,  irregular,  or  intermittent,  and  may 
be  influenced  by  changes  in  irritability  and  conductivity.  If  the 
rate  is  changed,  it  must  be  either  slower  or  faster;  if  the  contrac- 
tility is  changed,  it  must  be  either  weaker  or  stronger.  If  there 
is  an  alteration  in  lone,  the  degree  of  relaxation  in  diastole  must 
be  either  greater  or  less. 

The  Vessels. —  The  Arteries. — Changes  in  the  caliber  of  the 
arterioles  may  be  local,  affecting  the  blood-supply  of  only  one 
or  two  organs,  or  may  be  general,  affecting  general  arterial  pres- 
sure. The  caliber  is  determined  by  the  activity  of  the  arterial 
muscles,  which,  by  their  contraction  narrow  the  lumen  of  the 
artery,  and  by  their  relaxation  widen  it. 

These  muscles  may  act  as  the  result  of  direct  stimulation  or 
depression,  or  in  response  to  impulses  received  through  the  vaso- 
motor  nerves.  Of  these  vasomotor  nerves  there  are  two  sets, 
the  vasoconstrictors  and  the  -vasodilators,  each  set  consisting  of 
center,  nerves,  ganglia,  and  the  nerve-endings  in  the  arterial 
muscles.  The  vasoconstrictor  centers  are  masses  of  cells  situated 


THE    PHYSIOLOGY    OF    THE    CIRCULATION  153 

on  both  sides  of  the  middle  line  in  the  medulla  oblongata;  the 
vasodilator  centers  are  scattered  masses  of  cells  in  various  parts 
of  the  central  nervous  system.  The  arterial  muscles  are  in  a 
constant  state  of  contraction  or  tone,  which  enables  them  to 
resist  the  bursting  pressure  of  the  fluid  within ;  and  this  resistance 
tone,  though  insured  to  a  slight  extent  by  the  inherent  nature  of 
muscle  which  makes  it  contract  in  response  to  a  demand  put 
upon  it,  is  due  in  very  large  measure  to  the  continuous  reception 
of  subminimal  impulses  from  the  vasoconstrictor  center.  Thus 
there  is  a  certain  amount  of  contraction  or  tone  normally  present 
in  the  arteries,  and  when  the  vasoconstrictor  centers,  ganglia, 
or  nerve-endings  are  depressed  by  drugs,  this  tone  is  lowered  and 
the  arteries  dilate. 

The  vasodilators  differ  from  the  vasoconstrictors,  for,  in  the 
first  place,  they  do  not  act  continuously,  but  only  under  special 
circumstances;  and,  secondly,  they  produce  dilatation  only  by 
inhibiting  the  contractile  impulses,  for  there  are  no  dilating 
muscles  in  the  arteries. 

Both  the  vasoconstrictor  and  the  vasodilator  nerves  belong 
to  the  sympathetic  system.  When  both  sets  are  stimulated  to- 
gether, the  vasoconstrictor  effect  prevails;  but  under  excessive 
or  prolonged  stimulation  the  vasoconstrictor  is  the  first  to  show 
exhaustion,  so  that  the  constriction  may  be  followed  by  wide 
dilatation,  even  the  intrinsic  tone  of  the  muscle-fibers  being 
probably  somewhat  inhibited. 

Like  the  vagus  and  accelerator  mechanisms,  the  vasomotor 
may  be  affected  by  remedies  acting  directly  upon  any  part  of  the 
vasomotor  system,  viz.,  center,  nerves,  ganglia,  or  nerve-endings; 
and  they  may  also  be  affected  reflexly  by  afferent  impulses  com- 
ing to  the  centers  from  other  parts  of  the  body. 

Besides  the  muscle  itself  and  the  vasomotor  nervous  mech- 
anisms, the  receptive  substance  at  the  neuromuscular  junction  has 
specific  properties,  and  may  be  the  site  of  action  of  a  drug. 

Summary. — The  arteries  may  be  contracted  by: 

1.  Direct  stimulation  of  their  muscle-fibers. 

2.  Direct    or    reflex    stimulation    of    the    vasoconstrictor 

nervous  mechanism,  or  the  neuromuscular  junction. 
The  arteries  may  be  dilated  by: 

1.  Direct  depression  of  their  muscle-fibers. 

2.  Direct    or    reflex    depression    of    the    vasoconstrictor 

nervous  mechanism. 

3.  Direct  or  reflex  stimulation  of  the  vasodilator  mechan- 

ism. 

Some  of  the  arteries  do  not  have  vasoconstrictor  nerves. 
At  least,  nerves  connected  with  the  vasoconstrictor  center  have 


154          PHARMACOLOGY  AND  THERAPEUTICS 

not  been  demonstrated  in  the  coronary  arteries,  those  of  the 
brain,  and  those  of  the  lungs.  (See  Howell.)  These  arteries, 
however,  maintain  their  intrinsic  tone. 

The  blood-supply  of  the  lieart  is  somewhat  intermittent,  and 
is  dependent  upon  a  proper  diastolic  pause,  for  during  the  greater 
part  of  systole  the  blood  is  squeezed  out  of  the  coronaries,  while 
during  the  diastolic  pause  the  coronaries  refill  from  the  aorta  and 
make  an  active  circulation  in  the  relaxed  heart.  Dilatation  of 
the  coronaries  is  frequently  brought  about  by  drugs  that  con- 
strict other  arteries.  In  the  brain  the  supply  of  the  blood  is 
largely  determined  by  the  rise  and  fall  of  general  arterial  pres- 
sure plus  the  influence  of  gravity.  Of  the  pulmonary  circula- 
tion we  shall  speak  later. 

The  caliber  of  the  cutaneous  arterioles  is  under  a  sensitive  con- 
trol mechanism  different  from  that  of  the  other  arterioles  of  the 
body,  so  that  their  dilatation  and  contraction  frequently  take 
place  independently  of  the  general  arteriole  system,  as  in  blush- 
ing. They  are  wreak  arteries,  however,  and  regularly  tend  to  be 
somewhat  dilated  when  general  arterial  pressure  is  high. 

The  veins  also  contain  muscles,  but  their  contraction  and 
dilatation  seem  to  be  of  little  moment  in  pharmacology.  The 
large  veins,  even  the  portal  vein,  as  demonstrated  by  Burton- 
Opitz,  are  scarcely  if  at  all  influenced  through  vasomotor  nerves. 
The  venous  system,  however,  forms  an  enormous  reservoir  for 
blood,  so  that  by  the  accumulation  of  blood  in  the  veins  the 
arterial  system  may  be  readily  depleted.  Venous  pressure 
varies  considerably,  that  in  the  superior  cava  being  alternately 
negative  and  positive,  and  that  in  the  inferior  cava  constantly 
positive  and  sometimes  as  high  as  50  or  60  mm.  of  mercury.  It 
must  be  remembered  that  the  period  of  filling  of  the  ventricle  is 
shortened  if  the  venous  pressure  is  high,  that  during  the  period  of 
diastasis  the  venous  onflow  in  the  large  veins  is  stopped,  and  that 
during  auricular  systole  there  is  some  reflux  into  the  great  veins. 

The  capillaries  have  no  muscles,  and  dilate  or  contract 
mechanically  as  more  or  less  blood  is  forced  into  them.  It  is 
their  function  to  serve  as  a  membranous  medium  of  exchange 
between  the  blood  and  the  tissue-fluids,  in  both  directions. 

Arterial  Pressure. — The  gross  factors  which  go  to  maintain 
arterial  pressure  are  four  in  number,  viz.,  the  arteriole  or  periph- 
eral resistance,  the  heart's  output  in  a  given  time,  the  volume  of 
blood  in  the  arteries,  and  the  viscosity  of  the  blood. 

The  pressure  may  be  lowered  by  general  dilatation  of  the 
arterioles,  by  decrease  in  the  heart's  output,  by  loss  of  blood  or 
the  fluid  of  the  blood,  and  slightly  by  a  decrease  in  viscosity. 
It  may  be  raised  by  general  contraction  of  the  arterioles,  by  in- 


THE    PHYSIOLOGY    OF    THE    CIRCULATION  155 

crease  in  the  output  of  the  heart,  by  the  addition  of  fluid  to  the 
blood,  and  by  an  increase  in  viscosity. 

The  most  important  regulators  of  arterial  pressure  are  the 
arterioles,  but  even  if  the  arterioles  remain  contracted,  pressure 
cannot  be  maintained  if  the  heart  gives  out  or  if  there  is  much 
loss  of  blood. 

Of  the  arterioles,  those  of  the  splanchnic  area  have  most  to 
do  with  the  regulation  of  arterial  pressure.  They  are  strongly 
muscular,  are  abundantly  supplied  with  nerves  so  that  they  are 
readily  influenced,  and  have,  when  dilated,  an  enormous  capacity. 
Indeed,  when  these  arteries  are  much  relaxed,  so  much  blood 
passes  into  them  that  the  brain  may  be  depleted,  with  fainting 
or  even  death  as  the  result,  so  that  a  person  may  be  said  to  bleed 
into  his  own  splanchnic  arteries.  On  the  contrary,  they  may  be 
so  strongly  contracted  that  the  weaker  arteries  of  the  limbs  and 
skin  are  forced  to  dilate  to  accommodate  the  blood. 

It  is  to  be  noted  that,  so  far  as  life  is  concerned,  the  main- 
tenance of  adequate  cerebral  and  coronary  circulation  is  the  es- 
sential, for  upon  these  depends  the  activity  of  the  vital  centers 
in  the  medulla  and  of  the  heart.  Many  times  it  is  in  response  to 
the  needs  of  the  vital  centers  that  physiologic  changes  in  the 
caliber  of  the  arteries  take  place.  The  needs  of  other  parts  of 
the  body,  such  as  the  kidneys,  may  also  greatly  influence  the 
general  arterial  pressure.  Hence  reduction  of  what  seems  ab- 
normally high  arterial  pressure  may  result  in  a  failure  of  these 
organs  to  functionate.  (For  a  resume  of  theories  relating  to 
high  pressure  in  kidney  disease  see  Janeway's  Harvey  Society 
Lecture,  1913.) 

The  Pulmonary  Circulation. — The  pulmonary  arteries  have 
no  vasoconstrictor  nerves,  but  maintain  an  intrinsic  muscular 
tone  of  moderate  degree.  They  transmit  just  as  much  blood  as 
the  systemic  arteries,  for  since  the  system  is  essentially  a  closed 
one,  just  as  much  blood  must  be  pumped  by  the  right  ventricle 
as  by  the  left  ventricle,  minus  a  slight  loss  from  the  lung  capil- 
laries. But  the  thin  walls  and  feebler  muscle  of  the  right  ven- 
tricle and  the  inability  of  the  tricuspid  valve  to  withstand  high 
pressures,  show  that  less  power  is  required  in  the  transmission  of 
the  blood,  and  it  is  evident  that  the  pulmonary  arteries  give  little 
resistance  to  the  blood-flow.  It  is  estimated  that  the  normal 
pulmonary  arterial  pressure  is  only  one-seventh  to  one-third  that 
in  the  aorta. 

In  certain  cardiac  affections,  however,  where  there  is  back 
pressure  on  the  pulmonary  circulation,  as  in  obstruction  at  the 
mitral  valve,  the  right  ventricle  becomes  thick  and  strong  and 
its  cavity  larger,  and  the  pulmonary  pressure  may  rise  so  high 


156  PHARMACOLOGY  AND  THERAPEUTICS 

as  to  rupture  one  or  more  of  the  smaller  arteries  of  the  lungs. 
Such  a  pressure  is  mechanical,  depending  upon  two  factors,  viz., 
increased  output  of  the  right  ventricle  and  obstruction  to  the 
onward  flow  of  blood  in  the  left  heart. 

So  far  as  we  know,  all  drugs  which  affect  the  left  ventricle 
will  proportionately  affect  the  right  ventricle;  and  no  difference 
has  been  noted  except  in  those  rare  cases  in  which,  through 
organic  narrowing  or  impairment  of  contractility  in  one  coronary, 
the  other  only  is  affected  by  the  drug.  The  degree  of  filling  of 
the  right  ventricle  depends  upon  the  amount  of  venous  pressure 
versus  the  tone  of  the  heart  muscle.  The  rapidity  of  filling 
increases  with  the  venous  pressure  (Hirschf elder). 

Compensation. — A  term  much  employed  in  connection  with 
disturbances  of  the  circulation  is  "compensation,"  which  refers 
to  the  ability  of  the  heart  to  maintain  arterial  pressure  in  spite 
of  some  condition  or  lesion  which  tends  to  make  the  arterial 
pressure  low.  It  is  the  ability  of  the  heart  to  compensate  for 
some  leakage  or  other  adverse  condition.  We  speak  of  the  lack 
or  failure  of  compensation  when  the  heart  is  unable  to  maintain 
adequate  arterial  pressure.  The  effects  of  failure  of  compensa- 
tion are:  (i)  General  venous  and  pulmonary  engorgement,  with 
lymphatic  damming  up  and  a  tendency  to  edema  and  dropsy. 
(2)  Diminished  supply  of  blood  to  the  organs.  (3)  Poor  aera- 
tion of  the  blood  on  account  of  the  sluggish  pulmonary  circula- 
tion. The  symptoms  are:  Labored  breathing,  inability  to  lie 
flat,  weak  and  dilated  heart,  rapid  pulse,  sluggish  peripheral 
circulation  with  cold  extremities,  cyanosis,  and  perhaps  edema 
or  dropsy. 

Ordinarily,  when  a  lesion,  e.  g.,  a  defective  valve,  would  tend 
to  interfere  with  the  heart's  ability,  there  is  a  natural  compen- 
satory hypertrophy  of  the  muscle  and  a  compensatory  enlarge- 
ment of  one  or  other  of  its  cavities,  which  is  spoken  of  as  "dilata- 
tion"; so  that  in  spite  of  quite  a  marked  lesion  of  the  heart, 
compensation  may  be  maintained.  Thus  if  there  is  a  lesion  of 
the  mitral  valve  which  permits  leakage,  then  at  each  systole 
some  of  the  blood  from  the  ventricle  is  forced  back  through  the 
leaking  valve  into  the  auricle,  instead  of  forward  into  the  sys- 
temic arteries.  In  consequence,  the  heart  would  not  be  able  to 
keep  up  the  systemic  circulation  were  it  not  for  the  fact  that  in 
response  to  requirement  the  cavity  of  the  ventricle  becomes 
more  capacious,  and  the  muscular  walls  become  hyper trophied, 
so  that  the  heart  can  pump  more  blood  at  each  systole.  It  thus 
provides  for  the  needs  of  the  systemic  circulation  in  addition  to 
the  leakage.  In  other  words,  by  dilatation  and  hypertrophy 
the  heart  compensates  for  the  loss  by  leakage. 


DIGITALIS  157 

Sooner  or  later,  however,  the  lesion  extends  beyond  any 
power  of  natural  compensation;  or  for  some  other  reason,  usually 
a  change  of  rhythm,  the  muscle  fails,  and  then  there  is  failure 
of  compensation.  A  condition  of  threatened  failure  of  compensa- 
tion may  exist  when  the  heart  is  on  the  brink  of  failure,  but 
remains  adequate  so  long  as  special  pains  are  taken  to  pro- 
tect the  body  from  effort.  In  these  cases  there  is  no  reserve 
force,  and  failure  is  constantly  threatened. 

Mackenzie  perhaps  expresses  these  ideas  better  by  assuming 
that  the  power  of  the  heart  may  be  divided  into  a  working  force 
and  a  rest  force.  The  rest  force  is  that  which  meets  the  needs  of 
the  body  at  rest,  while  the  working  force  meets  the  additional 
requirements  when  the  body  is  engaged  in  effort.  The  begin- 
ning of  heart  weakness  would  then  be  evidenced  by  limitation  of 
the  working  force.  It  might  show  by  discomfort  or  distress  in 
performing  some  act  which  formerly  gave  no  distress,  e.  g.,  short- 
ness of  breath  on  going  up  stairs,  on  running,  or  on  lifting  a  heavy 
weight.  The  working  force  may  be  encroached  upon  to  any 
degree,  even  to  its  exhaustion,  but  if  the  rest  force  remains,  the 
patient  may  still  maintain  an  adequate  circulation  if  put  to  bed 
and  kept  from  effort.  When  the  rest  force  is  cut  down,  there  is 
serious  failure  of  compensation,  with  the  consequences  as  detailed 
above. 

THE  GENERAL  CIRCULATORY  STIMULANTS 

Besides  drugs,  various  remedial  measures  are  adopted  in  the 
treatment  of  failing  circulation,  such  as  rest  in  bed,  light,  non- 
fermenting  diet  with  restriction  of  liquids,  the  cold  bath,  the 
Nauheim  bath,  cold  air,  regulated  exercises,  etc. 

The  Nauheim  bath  is  a  saline  bath  in  the  water  of  which  car- 
bon dioxide  is  set  free.  It  tends  to  raise  the  arterial  pressure,  in 
some  cases  to  a  dangerous  degree. 

The  drugs  of  the  class  are :  Digitalis  and  its  allies  (strophanthus, 
convallaria,  etc.),  epinephrine,  ammonia,  and  possibly  camphor. 
There  are  a  few  others,  such  as  caffeine,  whose  dominant  actions 
place  them  more  properly  in  other  groups. 

DIGITALIS 

Digitalis  (Lat.,  digitalis),  or  foxglove,  is  the  dried  leaves  of 
Digitalis  purpurea  (Fam.  Scropkulariace(E).  It  is  an  ornamental 
flower  of  the  gardens,  grows  wild  in  Europe,  Oregon,  and  Aus- 
tralia, and  is  cultivated  for  the  drug  market  in  England  and 
Germany.  The  wild  American  plant  has  been  found  efficient. 

Constituents. — The  active  principles  are  glucosides,  and  are, 


158  PHARMACOLOGY    AND    THERAPEUTICS 

therefore,  subject  to  ready  destruction.  Digitoxin,  which  most 
nearly  represents  the  digitalis  action,  is  practically  insoluble  in 
water,  but  soluble  in  alcohol.  It  is  present  to  the  extent  of 
0.2  to  0.4  per  cent.  Digitalin,  next  in  importance,  is  slightly 
soluble  in  water,  soluble  in  100  parts  of  diluted  alcohol,  and  read- 
ily in  alcohol.  Digitalein,  of  similar  nature,  is  soluble  in  both 
water  and  alcohol.  Under  the  influence  of  heat  or  acids,  or 
when  kept  some  time  in  aqueous  solution,  as  in  the  infusion, 
these  glucosides  tend  to  decompose,  and  may  form  toxiresins 
which  have  a  central  convulsant  action. 

In  addition  to  these  active  principles,  digitalis  contains 
digitonin,  a  saponin  body  which  foams  with  water  and  possesses 
the  peculiar  property  of  holding  the  otherwise  insoluble  active 
principles  in  solution  in  water.  It  is  on  account  of  this  that  the 
infusion  of  digitalis,  an  aqueous  preparation,  represents  the 
activity  of  the  drug.  Digitonin,  administered  intravenously, 
is  a  physiologic  antagonist  of  digi toxin;  but  it  is  not  absorbable 
from  the  alimentary  tract.  It  crystallizes  from  solutions  in 
alcohol  of  over  85  per  cent,  strength.  Besides  these  principles, 
digitalis  contains  an  acrid,  nauseating  substance,  digilalosmin, 
free  oil,  and  digitaleic  acid. 

Preparations  and  Doses.— Official. — Digitalis,  dose,  i  grain 
(0.06  gm.).  Fluidextract,  i  minim  (0.06  c.c.).  Tincture,  10 
per  cent.,  10  minims  (0.6  c.c.).  Infusion,  1.5  per  cent.,  i  dram 
(4  c.c.).  The  doses  above  may  be  increased  up  to  four  times 
as  much  in  serious  cases.  The  Pharmacopoeia  requires  a  biologic 
assay  for  all  digitalis  preparations. 

Unofficial. — Digitoxin,  dose,  y^-g-  grain  (0.0005  gm-)>  is  too 
irritating  for  hypodermatic  use,  but  may  be  used  by  mouth  or 
intravenously. 

Digitalin,  dose,  yV  grain  (0.006  gm.),  is  moderately  irritating, 
but  can  be  used  hypodermatically.  (See  page  161 .) 

Digalcn,  made  according  to  Cloetta's  formula,  is  a  proprietary 
remedy  which,  it  is  claimed,  contains  ^-g  grain  (0.3  mg.)  of 
digitoxin  in  each  15  minims  (i  c.c.),  the  solvent  being  alcohol, 
glycerin,  and  water.  A  number  of  investigators  believe  that 
this  is  not  digitoxin,  but  probably  digitalein.  It  is  moderately 
irritating,  but  has  been  used  intravenously.  Laboratory  experi- 
ments show  its  action  to  be  very  variable. 

Digipuratum,  made  according  to  Gottlieb's  formula,  is  an 
extract  freed  from  digitonin  and  most  of  the  extractive  matter, 
and  mixed  with  sugar  of  milk  to  form  a  powder  of  the  same 
strength  as  digitalis  leaves.  Worth  Hale  and  others  have  found 
it  a  good  preparation.  In  our  own  experience  it  is  exceedingly 
uniform.  It  is  marketed  in  tablet  and  in  o.i  per  cent,  solution 


DIGITALIS  159 

of  sodium  bicarbonate.  The  tablets  are  equivalent  to  if  grains 
(o.i  gm.)  of  digitalis.  The  liquid  form  is  for  intravenous  or 
hypodermic  use,  15  minims  (i  c.c.)  being  equivalent  to  if  grains 
(o.i  gm.)  of  digitalis.  Digifolin  is  a  similar  preparation  of  the 
same  strength. 

Eggleston  finds  that  the  total  amount  to  develop  effects  is  the 
same  whether  given  at  one  time  or  in  repeated  doses.  From  the 
large  doses  the  average  time  to  obtain  an  action  was  twenty-eight 
hours,  and  from  the  smaller  repeated  doses,  seventy  hours. 
He  found  that  the  full  dose  was  about  2  minims  (0.146  c.c.)  of  the 
tincture,  or  2~gV<y  grain  (0.023  mg-)  °f  digitoxin,  by  mouth,  per 
pound  of  body  weight. 

In  a  comparative  test  by  Edmunds  the  infusion  and  the  tinc- 
ture were  found  of  equal  efficiency  when  given  in  doses  corre- 
sponding with  the  amount  of  digitalis  used  in  their  making. 
Focke  (1909),  however,  found  the  infusion  regularly  about  20 
per  cent,  weaker  than  the  powdered  leaves;  and,  because  of  the 
method  of  its  manufacture,  it  is  probable  that  this  is  usually 
the  case.  The  tincture  and  infusion  are  the  best  official  prepara- 
tions. The  author  has  frequently  seen  the  infusion  prescribed  in 
half -ounce  doses.  This  is  equivalent  to  36  minims  of  the  tinc- 
ture, and  is  a  large  dose;  but  it  is  probable  that  in  serious  cases 
the  best  results  are  obtained  only  when  such  very  large  amounts 
are  employed  at  the  outset.  The  effects  of  these  large  doses  of 
the  infusion  have  frequently  been  compared  with  those  from 
small  doses  of  the  tincture,  naturally  to  the  disadvantage  of  the 
latter.  The  author  is  informed  that  when  the  infusion  is  pre- 
scribed a  number  of  druggists  dispense  a  diluted  fluidextract,  a 
most  reprehensible  practice. 

The  fluidextract  is  a  concentrated  preparation  with  a  small 
dose,  and  to  its  use  there  are  the  following  objections:  (i)  On 
account  of  the  small  amount  of  solvent,  there  is  uncertainty  that 
all  the  active  principles  of  the  drug  are  extracted  in  the  prepara- 
tion; (2)  precipitation  is  likely  from  inability  of  the  solvent  to 
hold  so  much  dissolved  matter;  (3)  deterioration  is  more  likely, 
as  the  solvent  is  insufficient  to  act  as  a  preservative;  (4)  very 
slight  evaporation  materially  changes  the  strength  of  the  prepara- 
tion; and  (5)  owing  to  the  smallness  of  the  dose,  it  is  difficult 
to  grade  the  dosage.  As  a  matter  of  fact,  Worth  Hale  had  digitalis 
leaves  made  into  tincture  and  fluidextract,  and  found  the  latter 
only  about  three  times  as  strong  as  the  former,  instead  of  ten 
times,  as  it  should  be.  Assays  of  commercial  preparations  have 
given  similar  findings.  Hence  the  fluidextract  should  be  abol- 
ished. 

Digitalis  Allies. — There  are  some  other  drugs  with  effects  of 


l6o  PHARMACOLOGY   AND    THERAPEUTICS 

the  digitalis  kind,  and  the  whole  group  is  known  as  the  digitalis 
group,  or  the  digitalis  series.  The  members  of  the  group  that 
are  employed  as  circulatory  stimulants  are  digitalis,  strophanthus, 
squill,  convallaria,  apocynum,  adonis,  and  their  active  prin- 
ciples, and  the  glucosides,  ouabai'n  and  hellebore'in.  Several 
other  drugs,  such  as  oleander,  cereus  grandiflorus,  and  erythro- 
phleum  (sassy  bark),  are  reputed  to  have  some  of  the  actions  of 
digitalis,  but  have  not  come  into  general  use. 

Strophanthus  (strophanthus),  "the  ripe  seed  of  Strophanthus 
Kombe  or  of  5.  hispidus  (Fam.  A pocynacece) ,  deprived  of  its 
long  awn,"  comes  from  a  woody  climbing  plant  of  eastern  Africa. 

Constituents. — The  seeds  contain  from  i  to  3  per  cent,  of  an 
active  body,  strophanthin.  This  is  either  a  single  glucoside 
(methyl-ouabain)  or  a  mixture  of  glucosides,  and  is  souble  in 
water  and  alcohol.  Strophanthus  is  relatively  much  more  toxic 
to  the  heart  muscle  than  digitalis,  as  shown  below. 

Preparations  and  Doses. — Strophanthus,  i  grain  (0.06 
gm.).  Tincture,  10  per  cent.,  10  minims  (0.6  c.c.).  Strophan- 
thin, I\-Q  grain  (0.0005  gm-)-  The  U.  S.  P.  requires  a  biologic 
assay. 

Convallaria  (not  official)  is  "the  dried  rhizome  and  roots  of 
Convallaria  majalis  (Fam.  Liliaceai)"  the  common  lily-of-the- 
valley,  which  grows  wild  in  Europe,  Asia,  and  the  Allegheny 
Mountains.  The  drug  contains  the  active  glucoside,  conval- 
lamarin,  and  a  saponin-like  glucoside  of  the  digitonin  type, 
convallarin.  The  fluidextract  is  employed,  dose,  10  minims 
(0.6  c.c.).  Convallaria  is  relatively  much  more  poisonous  than 
digitalis,  as  shown  below. 

Squill  (scilla),  dose  if  grains  (o.i  gm.),  contains  the  gluco- 
sides, scillai'n  and  scillitoxin,  bodies  of  uncertain  composition. 
It  has  for  preparations  the  fluidextract,  the  10  per  cent,  tinc- 
ture, the  10  per  cent,  vinegar  facetum),  and  the  three  expec- 
torant mixtures,  syrup  of  squill,  which  contains  45  per  cent,  of 
the  vinegar,  the  compound  syrup  of  squill,  which  contains  8  per 
cent,  of  the  fluidextract,  and  the  National  Formulary  prepara- 
tion, mistura  pectoralis  (Stokes'  expectorant),  which  contains  3.5 
per  cent,  of  the  fluidextract.  The  expectorant  effect  is  prob- 
ably the  result  of  a  nauseant  action  in  the  stomach.  The  U.  S.  P. 
requires  a  biologic  assay. 

Apocynum  (dogbane),  dose,  15  grains  (i  c.c.),  is  used  in  the 
form  of  the  fluidextract.  It  contains  a  non-glucosidal  body, 
cymarin,  which  is  used  in  dose  of  oiU  grain  (0.0003  gm-)>  and 
the  glucosides,  apocynin  and  apocynein. 

Adonis  vernalis  is  not  official.  Its  dose  is  10  grains  (0.6  gm.), 
and  it  is  employed  in  the  form  of  fluidextract  or  infusion.  Its 


DIGITALIS  l6l 

active  glucoside,  adonidin,  may  also  be  used  in  dose  of  TV  grain 
(0.006  gm.). 

Ouabam,  known  as  "crystalline  gratus  strophanthin,"  is  a 
stable  crystalline  glucoside  of  great  activity.  Its  lethal  dose  is 
that  of  strophanthin.  Because  of  its  stability  it  has  been  sug- 
gested as  a  standard  for  physiologic  comparison.  It  is  employed 
intravenously. 

The  Standardization  and  Permanency  of  Preparations.— 
Edmunds,  by  physiologic  assay  of  16  different  commercial 
samples  of  the  tincture  of  digitalis,  found  that  the  dose  necessary 
to  produce  systolic  standstill  in  a  20  gm.  frog  varied  from  0.08  c.c. 
of  the  strongest  to  0.29  c.c.  of  the  weakest.  A  tincture  made 
from  one  batch  of  drug  might  thus  have  three  or  four  times  the 
strength  of  one  made  from  another  batch  of  drug,  and  the  cor- 
rect dose  of  one  would  be  the  wrong  dose  of  the  other.  Haynes, 
Hale,  and  others  have  found  similar  variation.  In  addition,  all 
the  preparations  slowly  deteriorate  on  keeping.  It  is  because 
of  these  things  that  the  Pharmacopoeia  has  adopted  the  biologic 
assay,  by  the  "one-hour-frog"  method.  Unfortunately,  this 
method  is  not  of  use  for  the  comparison  of  different  drugs,  but 
only  for  comparison  of  different  preparations  of  one  drug. 

Houghton's  table  of  comparisons  of  the  minimum  fatal  dose 
of  official  preparations,  as  tested  by  the  frog  method,  is  as  follows: 

Digitalis Fluidextract 0.0015  c-c- 

Tincture 0.015  c-c- 

Extract 0.0005  Sm- 

Strophanthus Tincture 0.000083  c.c. 

Convallaria Fluidextract 0.00025  c.c. 

Squill Fluidextract 0.0012  c.c. 

This  would  make  the  relative  toxicity  of  equal  amounts  of  the 
drug  as  follows:  digitalis,  i  :  Strophanthus,  18.5;  convallaria,  6; 
squill,  1.2.  Hatcher's  figures  from  equal  amounts  by  intravenous 
dosage  in  the  dog  are:  digitalis,  i;  convallaria,  |;  apocynum, 
|;  squill,  gV-  These  figures  do  not  show  the  relative  clinical 
efficiency,  however,  but  only  their  relative  toxicity;  and  the 
clinical  closes  bear  no  relation  to  the  lethal  doses.  In  proportion 
to  the  therapeutic  dose,  except  by  intravenous  administration, 
digitalis  is  the  least  toxic  of  them  all. 

Worth  Hale's  comparison  of  active  principles  by  the  frog 
method  is  as  follows:  The  minimum  fatal  dose  of  strophanthin 
is  o.ooooon;  of  convallamarin,  0.00000475;  °f  digitoxin, 
0.0000085;  °f  French  digitalin,  0.000013;  of  cligitalein,  0.000024; 
of  German  digitalin,  0.00007.  This  would  make  the  relative 
toxicity  of  equal  amounts  as  follows:  digitoxin,  i;  strophan- 
thin, 8;  convallamarin,  2;  French  digitalin,  f;  digitalein,  \\ 


162  PHARMACOLOGY  AND  THERAPEUTICS 

German  digitalin,  £  approximately.  Hatcher's  comparison  of 
toxicities  in  cats  by  intravenous  administration  is:  ouabai'n,  4; 
digitoxin,  i;  scillitoxin,  i;  true  digitalin,  |;  convallamarin,  |; 
digitalein,  £;  German  digitalin,  £. 

As  to  the  reliability  of  preparations  of  strophanthus  we  have 
some  evidence.  Hatcher  tested  old  and  new  tinctures  of  stro- 
phantus,  and  tinctures  made  from  recently  imported  seeds  and 
from  very  old  seeds,  and  reported  them  as  being  fairly  uniform. 
He  claims  that,  unlike  digitalis,  strophanthus  does  not  deterio- 
rate with  age.  Houghton  reported  that  the  tinctures  of  stro- 
phanthus on  the  market  varied  so  that  the  strongest  were  three 
times  as  strong  as  the  weakest;  and  Edmunds,  in  testing  five 
specimens  of  the  tincture  by  their  power  to  bring  a  20  gm.  frog's 
heart  to  systolic  standstill,  found  the  strongest  four  times  as 
strong  as  the  weakest.  (It  took  0.0012  c.c.  of  the  strongest  and 
0.005  c-c-  °f  the  weakest.)  So  the  possibility  of  great  difference 
in  the  strengths  of  preparations  must  be  borne  in  mind,  and 
reliable  assays  taken  advantage  of  when  possible.  Houghton 
has  also  reported  that  he  has  found  wide  variation  in  the  activity 
of  commercial  strophanthins,  one  sample  being  90  times  as 
fatal  as  another. 

Pharmacologic  Action. — Local  Action. — Digitalis  has  no 
effect  on  the  unbroken  skin,  but  to  mucous  membranes  and  sub- 
cutaneous tissues  is  irritant.  When  administered  hypodermati- 
cally,  it  causes  pain  at  the  site  of  injection,  and  through  its  ir- 
ritant properties  may  cause  destruction  of  tissue,  with  the  forma- 
tion of  either  a  slough  or  a  sterile  abscess  (sterile  because  not  due  to 
pathogenic  bacteria).  In  a  sick  patient  a  number  of  such  irri- 
tative areas  are  sufficient  to  cause  fever  and  depressing  reflexes, 
or  at  least  much  discomfort,  so  that  the  hypodermatic  use 
of  digitalis  preparations  is  to  be  avoided  when  possible.  Of 
the  active  principles,  digitalein  is  the  least  irritating,  digitoxin 
the  most  irritating. 

Alimentary  Tract. — The  taste  is  bitter  and  unpleasant. 
Because  of  the  local  irritant  effect  in  the  stomach,  nausea  or  even 
vomiting  may  result.  But  in  practice,  this  nausea  and  vomiting 
usually  come  on  only  after  the  patient  has  been  taking  digitalis 
for  several  days;  and  this  is  because  their  chief  cause  is  not  the 
irritation  of  the  stomach,  but  stimulation  of  the  vomiting  center 
after  the  drug  has  become  absorbed.  This  stimulation  increases 
until  the  center  becomes  so  sensitive  that  the  slight  irritation 
of  each  subsequent  dose  results  in  nausea  or  vomiting,  and 
requires  that  the  administration  of  the  drug  be  stopped.  This 
undesirable  effect  is  thus  largely  central,  and  it  occurs  from  doses 
administered  intravenously,  hypodermatically,  or  by  rectum, 


DIGITALIS 


163 


as  well  as  those  administered  by  mouth.  But  a  sensitive  vomit- 
ing center  makes  the  stomach  highly  susceptible  to  local  irritants, 
hence  doses  by  mouth  are  more  prone  to  produce  vomiting  than 
doses  administered  in  other  ways. 

Upon  the  intestines  there  is  ordinarily  no  effect,  but  some- 
times, probably  either  from  the  local  irritation  of  unabsorbed 
drug  or  from  stimulation  of  the  motor  nerves  of  the  intestines 
(the  vagus  nerves),  or  perhaps  from  muscular  stimulation,  diar- 


^ 

Kj^r^\i\^ 


Fig.  5.  —  Tracings  showing  toxic  effects  of  digitalis. 

rhea  is  set  up.     Strophanthin  has  been  shown  to  be  a  direct 
stimulant  of  intestinal  muscle. 

Digitalis,  then,  has  decided  effects  upon  the  stomach  and 
intestines,  but  they  are  undesirable  ones.  Worth  Hale  has 
determined  that  in  a  period  of  three  hours  the  acid  of  the  gastric 
juice  invariably  causes  a  diminution  of  from  25  to  35  per  cent,  in 
the  activity  of  the  digitalis  and  strophanthus  glucosides.  He 
recommends  that  to  avoid  this  the  official  preparations  should  be 


164          PHARMACOLOGY  AND  THERAPEUTICS 

neutral;  and  should  be  administered  with  an  alkali,  and  not 
after  meals,  but  later,  when  the  gastric  acidity  is  low. 

Absorption  takes  place  from  the  intestines,  and  since  the  drug 
penetrates  the  tissues  very  slowly,  is  uncertain  in  rate  and  degree. 
Thus  twelve  to  thirty-six  hours,  and  sometimes  several  days, 
elapse  before  the  systemic  action  is  manifest.  Eggleston  states 
that  both  digitalis  and  digitoxin  are  probably  rapidly  and  fairly 
uniformly  absorbed  from  the  alimentary  canal  of  man,  but 
strophanthus,  strophanthin,  ouabai'n,  and  true  digitalin  are  poorly 


Fig.  6. — Tracings  showing  toxic  effects  of  digitalis. 

or  irregularly  absorbed  when  given  by  mouth.  After  deep  intra- 
muscular injections  the  effects  follow  more  rapidly;  but  even 
then,  owing  to  the  drug's  slow  diffusibility,  may  not  appear  for 
hours.  In  dogs,  intravenous  toxic  doses  will  produce  a  prompt 
response,  but  in  man  even  intravenous  administration  of  thera- 
peutic amounts  may  require  one-half  to  several  hours  for  measur- 
able results. 

Where   the   digitalis   principles   remain   is   not   yet   certain. 
Cloetta  found  no  digitoxin  in  the  heart  muscle  of  rats  and  frogs. 


DIGITALIS  165 

Hatcher  (1912)  states  that,  after  an  intravenous  injection  of 
a  fatal  dose  in  cats,  ouabai'n  leaves  the  blood  in  about  three 
minutes.  After  the  injection  of  double  the  lethal  dose  of  digi- 
toxin  death  takes  place  in  five  minutes;  and  from  an  over- 
whelming dose,  may  take  place  during  the  administration; 
from  less  than  the  fatal  dose  some  of  the  effect  may  persist  for 
three  or  four  weeks. 

Circulation. — In  a  laboratory  animal  it  is  observed  that  a 
good-sized  dose  of  digitalis  has  profound  effects  upon  the  circu- 
lation. The  striking  laboratory  effects  are  given  under  Tox- 
icology. In  both  the  laboratory  animal  and  in  man  the  circula- 
tory effects  are  known  to  be  brought  about  through  action  upon 
five  different  structures.  These  structures  are  the  sinus  node, 
the  cardiac  muscle,  the  auriculo ventricular  bundle,  the  coronary 
arteries,  and  the  systemic  arteries.  The  effects  are  both  nervous 
and  muscular.  The  following  are  noted  in  man: 

A.  The  Sinus  Node. — This  is  believed  to  be  the  normal 
controller  or  pacemaker  of  the  rate  of  the  heart.  From  it 
impulses  are  given  to  the  auricles  at  more  or  less  regular  inter- 
vals of  time,  and  normally  at  the  rate  of  about  72  in  a  minute. 
In  response  to  these  impulses  the  auricles  contract  together  and 
are  followed  in  about  one-fifth  of  a  second  by  contraction  of  the 
ventricles  together.  A  rhythm  essentially  under  the  control 
of  sinus  impulses  is  known  as  "normal  rhythm." 

Slowing. — One  effect  of  the  administration  of  digitalis  is  to 
inhibit  or  retard  the  projection  of  impulses  by  the  sinus  node, 
the  result  being  slowing  in  the  rate  of  the  whole  heart.  There 
may  be  a  sino-auricular  heart-block.  The  same  type  of  slowing 
may  be  produced  by  stimulation  of  a  vagus  nerve  as  is  observed 
in  man  by  pressure  on  the  vagus  nerve  in  the  neck,  or  in  animals 
by  electric  stimulation  of  the  peripheral  segment  of  a  cut  vagus. 
Whether  the  slowing  results  from  electric  or  mechanical  vagus 
stimulation  or  from  digitalis,  it  is  abolished  by  atropine,  which 
paralyzes  the  vagus  nerve-endings  in  the  heart.  Thus  we  have 
evidence  that  digitalis  slowing  may  be  identical  with  that  from 
vagus  stimulation.  (See  "effect  on  auriculoventricular  bundle.") 

Again,  in  an  animal  with  vagus  nerves  cut,  or  in  an  isolated 
heart,  i.  e.,  a  heart  severed  from  all  its  connection  with  the  centers, 
the  digitalis  slowing  is  very  slight.  This  is  evidence  that  the 
essential  slowing  from  digitalis  does  not  come  from  action  on  the 
sinus  node  directly,  but  from  action  on  the  vagus  centers.  In 
other  words,  the  effects  are  vagus  effects,  and  they  are  not  to  any 
great  extent  produced  when  the  heart  is  severed  from  connection 
with  the  vagus  centers.  Therefore  we  have  the  evidence  that,  in 
a  heart  with  normal  rhythm,  digitalis  may  slow  the  rale  by  stimulat- 


1 66  PHARMACOLOGY   AND    THERAPEUTICS 

ing  the  vagus  centers.  There  is  probably  also  a  slight  stimulat- 
ing effect  on  the  ends  of  the  vagus  nerves,  but  this  is  not  im- 
portant. 

In  therapeutics  this  type  of  slowing  is  not  usually  obtained; 
but  it  may  be  a  toxic  manifestation  if  the  slowing  becomes  so 
marked  that  the  heart  does  not  beat  frequently  enough  to 
maintain  an  efficient  circulation.  As  a  matter  of  fact,  except 
in  auricular  fibrillation  or  auricular  flutter,  any  marked  degree  of 
slowing  is  not  a  usual  effect  from  the  therapeutic  use  of  digitalis, 
hence  absence  of  slowing  must  not  be  taken  as  an  indication  of  the 
drug's  inefficiency. 

Fever  and  old  age  have  been  said  to  counteract  the  vagus 
effects  of  the  drug,  but  in  105  pneumonia  cases  Cohn  and  Jamie- 
son  found  that  digitalis  acted  with  full  effect  even  though  the 
fever  was  high.  Jamieson  proved  the  same  in  other  acute  in- 
fections in  cats.  The  author  has  seen  pronounced  effects  in 
many  old  people. 

In  some  cases  it  is  possible  that  digitalis  causes  complete 
physiologic  standstill  of  both  auricle  and  ventricle  for  a  moment, 
as  is  seen  upon  electric  simulation  of  a  vagus  nerve,  but  this  has 
not  been  reported  as  a  digitalis  effect  in  man. 

Arhythmia. — Another  effect  of  digitalis  upon  the  sinus  node 
is  to  change  its  rhythmic  projection  of  impulses,  so  that  the 
heart-rate  shows  regularly  alternating  short  phases  of  accelera- 
tion and  slowing.  That  is,  the  rate  rhythmically  waxes  and 
wanes,  whether  the  total  rate  is  slowed  or  not.  This  is  also  the 
effect  of  vagus  stimulation,  and  it  is  abolished  by  atropine.  It 
is  known  as  sinus  arhythmia  or  phasic  arhythmia.  During 
forced  inspiration  and  expiration  this  arhythmia  is  physiologic, 
and  may  be  observed  in  most  people,  the  phases  corresponding 
with  the  phases  of  respiration.  But  when  it  results  from  digi- 
talis it  sometimes  has  no  relation  to  the  respiratory  rhythm; 
it  is  then  an  indication  of  beginning  poisoning. 

Summary. — Through  the  sinus  node  the  digitalis  effects  are 
either  slowing  of  the  rate  or  sinus  arhythmia,  or  both,  or  pos- 
sibly momentary  standstill.  They  result  from  vagus  stimula- 
tion. 

B.  The  Cardiac  Muscle. — The  striking  properties  of  the 
heart  muscle,  as  viewed  pharmacologically,  are  tonicity,  con- 
tractility, irritability,  and  stimulus  production. 

i.  Contractility  and  Tonicity. — Tonicity  of  muscle  is  its  prop- 
erty of  maintaining,  during  its  resting  period,  a  state  of  partial 
contraction  or  incomplete  relaxation,  i.  e.,  a  state  of  tone,  which 
keeps  it  in  readiness  to  respond  promptly  when  a  stimulus 
comes.  In  a  hollow  organ  like  the  heart  the  tone  gives  it  resistance 


DIGITALIS 


i67 


Normal 


Weak  and  dilated 


to  a  bursting  pressure  during  the  period  when  the  organ  is  not 
actively  contracting.  It  is  measured  by  the  degree  of  relaxation 
in  diastole.  Contractility  is  the  power  to  contract  against 
resistance.  It  is  measured  by  the  size  of  the  heart  at  the  end  of 
systole.  Tonicity  differs  from  contractility,  which  has  to  do 
with  the  active  contraction,  and  from  irritability,  which  deals 
with  sensitiveness  to  stimuli. 

In  a  heart  whose  contractility  and  tonicity  are  below  the 
normal,  the  ventricular  chambers  are  dilated  and  weak,  so  that  in 
diastole    the    muscle    is    stretched 
beyond  the  normal  by  the  venous 
inflow,    and   in    systole    contracts 
feebly.     The  result  is  a  decreased 
output  of  blood. 

If  we  take  two  concentric 
spheres  and  let  one  represent  the 
capacity  of  the  heart  during  the 
resting  period  of  diastole,  and  the 
other  the  capacity  at  the  end  of  sys- 
tole, we  might  represent  the  normal  and  the  weak  heart,  as  in  the 
illustration,  the  diminished  excursion  of  the  muscle  in  the  -latter 
lowering  the  output.  Digitalis,  by  increasing  the  tone  and  con- 
tractility, tends  to  bring  the  heart  muscle  back  to  normal,  and  so 
increases  the  output.  Its  site  of  action  in  producing  this  effect  may 
be  determined  by  administering  a  large  dose  of  atropine  to  a  labor- 
atory animal  to  eliminate  vagus  effects,  and  a  dose  of  apocodeine 


Fig.  7. — D,  Capacity  at  end 
of  diastole;  5,  capacity  at  end  of 
systole. 


Fig.  8. — Diagram  to  illustrate  "ventricular  extrasystole."  As,  Auricular  sys- 
toles; Vs,  ventricular  systoles.  At  x  the  ventricle  beats  spontaneously.  This 
beat  is  followed  by  a  refractory  period,  during  which  the  regular  auricular  im- 
pulse is  ineffective,  and  the  ventricle  does  not  beat  until  the  next  auricular  im- 
pulse. The  auricle  beats  regularly  throughout. 

to  cut  off  the  accelerators.  All  influences  through  the  nervous 
system  are  thus  removed,  but  digitalis  still  results  in  striking 
increase  in  contractility  and  tonicity.  It  must,  therefore,  stimu- 
late the  muscle  itself.  It  gives  these  effects  with  decided  force 
in  the  laboratory,  and  probably  to  some  extent  in  therapeutics. 

The  right  ventricle,  though  its  muscular  wall  is  normally  much 
thinner,  is  stimulated  as  much  proportionally  as  the  left. 

The  papillary  muscles  are  also  strengthened  and  toned,  a 


1 68 


PHARMACOLOGY    AND    THERAPEUTICS 


matter  of  special  importance  in  a  weak,  dilated  heart.     For 
these  muscles  must  contract  coincidentally  with  the  ventricle,  or 


Fig.  Q. — Ventricular  cxtrasystoles  developing  in  a  heart  with  normal  rhythm  and 
moderate  dilatation.  This  resulted  from  10  minims  (0.7  c.c.)  of  tincture  of  digi- 
talis and  20  minims  (1.3  c.c.)  of  tincture  of  nux  vomica  three  times  a  day.  It 
ceased  within  two  days  of  stopping  the  medicine.  (Top  line,  apex;  lower,  radial 
pulse.) 

they  will  allow  the  valves  to  bulge  into  the  auricle  during  systole 
and  make  a  relative  insufficiency,  i.  e.,  a  leakage  backward.  As 

a  matter  of  fact,  the  normal 
ventricular  contraction  begins 
in  the  papillary  muscles. 

An  effect  on  the  electrocar- 
diograph record  regularly  ob- 
tained after  digitalis  is  attrib- 
uted by  Cohn  to  a  probable 
action  on  contractility  (see  page 
178,  Fig.  22). 

2.  Irritability  or  excitability 
is  the  susceptibility  to  stimuli. 
Normally,  it  does  not  deter- 
mine the  rate  of  the  heart,  for 
the  normal  pacemaker  is  the 
sinus  node.  But  an  increase  of 
irritability  beyond  the  normal 
tends  to  result  in  spontaneous 
muscular  contractions  that  do 
not  have  their  origin  in  the 
sinus  node.  The  effects  of  these 
are  harmful.  They  may  be 

produced  by  digitalis.  Excessive  irritability  may  be  confined  to 
a  small  area  and  yet  be  the  cause  of  abnormal  beats,  "normally 
inactive  points  in  the  heart  taking  on  the  power  of  originating 
stimuli"  (Cushny). 


Fig.  10. — From  same  case  as  Fig.  Q. 
Every  fourth  beat  is  premature.  Top 
line-,  jugular;  middle,  apex;  lower, 
radial. 


DIGITALIS 


169 


Overirritability  or  aver  excitability  may  show  in  auricular  or 
ventricular  premature  beats,  in  paroxysms  of  tachycardia,  in 
auricular  flutter,  in  auricular  fibrillation,  or  in  ventricular  fibrilla- 
tion. In  some  excitable  hearts  there  are  alternations  of  premature 
beats,  paroxysmal  tachycardia,  and  auricular  fibrillation. 

(a)  Premature  Beats. — One  of  the  earliest  indications  of 
excessive  irritability  is  the  so-called  extrasystole,  a  prema- 
ture or  interpolated  beat  which  has  its  origin  elsewhere  than 


Fig.  ii. 


Fig.  12. 


Figs,  ii,  12,  and  13. — Auricular  fibrillation  and  complete  heart-block  develop- 
ing in  a  case  of  cirrhosis  of  liver,  with  weak  heart,  but  with  normal  rhythm. 
Digipuratum,  i\  grains  three  times  a  day,  was  given  from  April  iyth  to  2oth, 
when  tracing  showed  auricular  fibrillation  and  complete  heart-block,  rate  42. 
The  drug  was  stopped,  and  two  days  later  tracing  12  showed  auricular  fibrilla- 
tion alone,  rate  about  135.  Tracing  13  taken  the  next  day  showed  return  to 
normal  rhythm,  rate  100.  Similar  phenomena  followed  the  administration  of  dig- 
italis a  month  later. 

at  the  sinus  node.  The  site  of  origin  may  be  the  auricle,  the 
result  being  a  premature  auricular  beat,  usually  followed  by  a 
corresponding  premature  ventricular  beat  in  response  to  the 
auricular  stimulus.  But  much  more  commonly  the  premature 
beat  has  its  origin  in  the  ventricle,  the  ventricle  alone  giving  a 
premature  beat,  while  the  auricular  rhythm  is  not  affected.  A 


170  PHARMACOLOGY    AND    THERAPEUTICS 

premature  beat  may  appear  at  regular  intervals  or  irregularly, 
and  frequently  or  infrequently.  It  may  follow  the  normal  beats 
so  that  the  ventricle  beats  in  couples.  It  may  show  in  the 
radial  pulse  or  it  may  not,  but  it  is  an  irregularity  of  the  heart 
and  not  an  intermittence.  In  susceptible  hearts  it  may  some- 
times accompany  or  follow  holding  the  breath.  It  is  one  of  the 
most  commonly  observed  of  the  toxic  manifestations  of  digitalis. 
(b)  In  auricular  fibrillation  the  auricular  muscle  is  in  a  state 
of  such  excitability  that  muscle  groups  here  and  there  contract 
independently,  i.  e.,  the  fibers  quiver  or  fibrillate,  instead  of  con- 
tracting coordinately  to  make  an  auricular  beat.  The  fibrilla- 
tions occur  at  the  rate  of  several  hundred  per  minute,  and  their 
effect  upon  the  ventricle  is  to  make  it  beat  in  a  rapid,  irregular, 
and  disorderly  manner.  In  a  pulse-tracing  of  this  condition 
unmodified  by  drugs — (a)  No  two  sections  are  alike,  the  radial 
pulse  being  irregular  and  disorderly;  (6)  the  height  of  the  pulse 
wave- has  no  definite  relation  to  the  length  of  the  preceding  pause; 


Fig.  14. — Extrasystoles  and  auricular  flutter.  Case  with  auricular  fibrillation. 
Digitalis,  15  grains  four  times  a  day  for  four  days,  resulted  in  alternating  periods 
of  halving  of  the  pulse-rate  due  to  extrasystoles  (ventricle  140,  pulse  70),  and 
very  rapid,  almost  regular  pulse  at  the  same  rate  as  the  ventricle  186,  and  half 
the  rate  of  the  auricle  372  (auricular  flutter). 

and  (c)  the  jugular  tracing  shows  absence  of  the  normal  auricular 
waves,  and  in  some  instances  numerous  small  fibrillation  waves. 
Auricular  fibrillation  may  exist  without  serious  symptoms, 
but  it  is  usually  serious,  is  one  of  the  most  frequent  causes  of 
lack  of  compensation,  and  may  be  the  precursor  of  ventricular 
fibrillation  and  death. 

(c)  In  paroxysmal  tachycardia  the  heart  is  regular  or  nearly 
so,  but  very  rapid,  the  rate  usually  being  over  150.  The  beats 
may  have  their  origin  in  the  auricle,  in  the  ventricle,  or  at  the 
auriculoventricular  node.  If  the  tachycardial  beats  originate 
in  the  auricle  it  is  known  as  "auricular  flutter."  If  the  beats 
originate  at  the  auriculoventricular  node,  there  is  true  nodal 
rhythm,  and  the  auricle  and  ventricle  receive  their  stimulus  at  the 
same  time,  and  consequently  beat  simultaneously.  If  the 


DIGITALIS 


171 


beats  originate  in  the  ventricle,  there  may  be  a  reversed  or  retro- 
grade rhythm,  the  excitable  ventricle  beating  prematurely  and 
imposing  its  rhythm  upon  an  auricle  in  a  similar  state  of  excit- 
ability. The  ventricle  may  pass  into  a  state  of  fibrillation, 
which  almost  invariably  means  immediate  death. 

(d)^  Ventricular  fibrillation  is  the  usual   terminal  effect  of 
digitalis    poisoning    in    mammal    experiments    (Cushny).     It 


Fig-  is- 


U     V    ;      LJ      v. 


Fig.  1 6. 

Figs.  15  and  16. — Complete  heart-block.  Developing  after  digipuratum,  i£ 
grains  three  times  a  day  for  nine  days.  Fig.  16  shows  return  to  normal  rhythm 
after  the  digitalis  effect  had  worn  off.  This  block  was  suspected  when  a  pulse  that 
had  been  beating  between  106  and  116  for  several  days  suddenly  changed  to  a  rate 
between  60  and  70.  The  auricle  was  not  slowed. 

corresponds  in  mammals  with  the  continuous  systole  in  cold- 
blooded animals.  It  usually  leaves  the  mammal  heart  in  a 
state  of  diastolic  relaxation,  but  Eckler  (1912)  reports  that  after 
death  from  digitalis,  strophanthus,  and  ouabai'n,  12  out  of  62 
mammal  hearts  were  found  in  systolic  contraction. 

C.  The  Auriculoventricular  Bundle. — The  function  of  this 
bundle  is  to  conduct  impulses  from  the  auricle  to  the  ventricle, 
so  that  normally  the  ventricular  beat  follows  that  of  the  auricle 


172  PHARMACOLOGY   AND    THERAPEUTICS 

in  practically  one-fifth  of  a  second.  The  effect  of  digitalis  on 
this  bundle  may  be  the  retardation  or  prevention  of  conduction. 
This  is  usually  a  result  of  vagus  stimulation,  and  it  may  be  pre- 
vented by  atropine.  But  in  some  cases,  as  demonstrated  by 
Cushny,  the  effect  of  digitalis  on  conduction  is  not  prevented  by 
atropine,  and  in  these  digitalis  presumably  has  a  direct  action 
upon  the  junctional  tissues,  either  the  auriculoventricular 
bundle  proper,  or  the  junctions  of  its  ramifications  with  the  proper 
muscles  of  the  ventricles. 

In  therapeutics  a  prolongation  of  the  auriculoventricular 
interval,  e.  g.,  to  three- tenths  or  three-fifths  of  a  second  (incipient 
heart-block],  is  not  uncommon  from  digitalis.  It  is  an  effect  that 
can  be  ascertained  only  by  tracings,  but  it  is  a  toxic  manifesta- 
tion and  calls  for  stoppage  of  the  drug.  More  rarely  seen  from 
digitalis,  but  much  more  serious,  is  a  degree  of  interference  with 
conduction  which  results  in  occasional  or  frequent  failure  of  the 
ventricle  to  beat  in  response  to  the  auricle,  i.  e.,  a  state  of  partial 
heart-block.  In  this  the  auricle  beats  faster  than  the  ventricle. 
In  mild  degrees  the  auriculoventricular  interval  gradually 
lengthens,  or  suddenly  lengthens,  so  that  the  ventricle  intermits 
at  regular  intervals,  i.  e.,  skips  every  tenth,  seventh,  third,  etc., 
beat,  the  tracings  showing  an  independent  auricular  beat  during 
the  ventricular  intermission;  and  the  stethoscope  no  ventricular 
contraction.  In  marked  stages  the  ventricle  beats  only  in 
response  to  every  second  or  third  auricular  beat,  i.  e.,  in  2  :  i  or 
3  :  i  rhythm,  the  pulse  being  slow  and  regular.  In  these  last 
states  fainting  spells  are  not  uncommon. 

Still  less  frequent  from  digitalis  is  complete  heart-block,  in 
which  the  ventricle  receives  no  adequate  stimulus  from  the  auricle, 
and  consequently  beats  at  its  own  intrinsic  rate,  with  entire 
disregard  of  the  auricular  beat.  In  the  complete  block  of  dis- 
ease the  rate  of  the  ventricle  is  in  the  neighborhood  of  30,  and 
this  is  the  normal  intrinsic  rate  of  the  human  ventricle.  But  in 
the  complete  block  from  digitalis,  owing  to  the  increase  in  mus- 
cular irritability,  the  rate  tends  to  be  faster,  and  may  even  exceed 
that  of  the  auricle  (Hewlett  and  Barringer).  In  this  last  type, 
in  the  absence  of  a  careful  study  of  tracings,  the  block  may  re- 
main undetected.  In  ordinary  cases,  however,  bradycardia 
should  suggest  the  possibility  of  block ;  and  in  any  heart  a  block 
should  always  be  suspected  when  there  is  a  sudden  slowing  of  the 
ventricular  rate  with  regularity.  In  auricular  fibrillation  a 
complete  block  is  shown  by  the  striking  change  from  rapidity 
and  irregularity  in  the  action  of  the  ventricle  to  slowing  and 
regularity.  Shining  from  digitalis  may,  therefore,  be  due  to 
aurkuloventricular  heart-block,  as  well  as  to  an  effect  upon  the 


DIGITALIS 


173 


sinus  node.  Indeed  it  is  to  this  cause  that  the  slowing  obtained 
in  auricular  fibrillation  or  flutter  is  due. 

When  a  partial  block  is  already  established  by  disease,  digi- 
talis is  very  prone  to  increase  its  severity  or  to  change  it  to 
complete  block.  Some  of  the  deaths  from  the  intravenous  use 
of  strophanthin,  the  digitalis  ally,  have  probably  been  produced 
in  this  way. 

The  following  is  an  interesting  case  of  permanently  complete 
heart-block,  in  which  the  digitalis  had  the  effect  of  bringing  on 


1 

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3 

4 

5 

6 

7 

ft 

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IQ 

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QC 

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26 

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34 

A 

}? 

\ 

3C 

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to 

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36 

i4 

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\ 

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70 

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\ 

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ifl 

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54 

*NS 

5? 

Fig.  17. — Chart  comparing  the  effect  of  digitalis  on  the  rate  in  cases  having 
auricular  fibrillation  with  those  having  a  normal  rhythm.  The  black  dots  repre- 
sent the  rate  with  auricular  fibrillation  and  the  white  with  the  normal  rhythm. 
The  side  figures  represent  pulse-beats.  The  top  figures  represent  days  (James 
Mackenzie  in  "Heart,"  vol.  ii,  No.  4,  1911). 

short  spells  of  doubling  of  the  intrinsic  rate  of  the  ventricle  with 
retrograde  rhythm.  It  was  a  case  on  Dr.  Nome's  service  at  St. 
Luke's  Hospital.  In  one  of  my  tracings  from  this  case  the  ven- 
tricular rate  shows  a  sudden  jump  from  26  to  54,  a  drop  of  the 
auricular  rate  from  62  to  54,  and  a  change  of  the  rhythm  to 
"reversed"  or  retrograde,  i.  e.,  the  auricular  systole  followed 


174  PHARMACOLOGY   AND    THERAPEUTICS 

that  of  the  ventricular,  instead  of  preceding  it,  both  having  the 
same  rate.  At  the  end  of  each  such  paroxysm  there  was  a  long 
pause  of  the  ventricle,  lasting  some  seconds,  during  which  the 
patient  had  a  passing  attack  of  faintness  or  light-headedness, 
though  lying  flat  in  bed. 

Such  a  pause,  sometimes  following  the  doubling  of  a  slow 
ventricular  rate,  is  prone  to  occur  in  partial  or  complete  heart- 
block,  and  may  be  accompanied  by  feelings  of  faintness,  loss  of 


y      y  \ 


Fig.  1 8. 


Fig.  IQ. 

FiRs.  18  and  19. — Complete  heart-block  developing  in  a  case  with  auricular 
fibrillation.  On  admission  (tracing  18)  the  ventricle  was  very  irregular,  rate  146  to 
200,  with  a  countable  radial  pulse  of  80  to  94.  Infusion  of  digitalis,  4  drams  thrice 
daily,  was  given  for  eleven  days,  then  stopped.  At  this  time  the  pulse  was  nearly 
regular,  rate  about  72.  Four  days  later  tracing  IQ  was  taken,  the  pulse  being  quite 
regular,  rate  54.  Three  days  later,  /.  c.,  one  week  after  the  stoppage  of  the  drug, 
the  complete  block  was  still  present,  the  ventricular  rate  remaining  between  50  and 
60. 

consciousness,  or  an  epileptiform  convulsion,  the  typical  Stokes- 
Adams  attack.  These  effects  are  due  to  a  momentary  anemia 
of  the  medullary  centers,  the  result  of  the  ventricular  stoppage. 
They  are  likely  to  be  more  serious  if  the  patient  is  in  the  upright 
position. 

D.  Combined  Effects. — In  cases  with  auricular  fibrillation 
already  established  from  disease  the  combined  effects  on  irri- 
tability and  conduction  are  strikingly  to  be  observed  after  digi- 


DIGITALIS 


175 


tails.  The  therapeutic  effect  of  the  drug  in  auricular  fibrillation 
is  not  to  overcome  the  fibrillation,  so  far  as  we  know,  but  essen- 
tially to  impair  conductivity.  It  thus  checks  the  passage  of  the 
frequent  small  and  irregular  auricular  impulses,  which  in  this 
condition  serve  only  to  nag  the  ventricle  and  make  its  action 
disorderly.  In  other  words,  it  establishes  a  degree  of  heart-block. 
The  effect  is  partly  due  to  vagus  stimulation,  and  pressure 
on  the  vagus  in  the  neck  will  sometimes  momentarily  produce 
a  similar  result,  while  atropine  will  prevent  it.  It  is  prob- 


Fig.  20. — Coupled  rhythm  developing  in  a  case  of  auricular  fibrillation.  This 
is  an  exceedingly  common  effect.  It  resulted  after  five  days  of  powdered  digitalis, 
2  grains  three  times  a  day. 


Fig.  21. — Phasic  arhythmia  developing  in  a  case  of  auricular  fibrillation. 
This  followed  digalen,  10  minims  every  four  hours,  for  one  day,  and  digipuratum, 
if  grains  three  times  daily  for  two  days.  Upper  line  shows  respiration,  which  is 
not  synchronous  with  the  phases  of  quickening  and  slowing  of  the  pulse. 

ably  also,  in  some  instances,  clue  to  a  direct  action  of  the  digitalis 
on  the  junctional  tissues  (Cushny).  The  block  may  become 
complete,  with  regularity  of  the  ventricular  beats  and  a  much 
slowed  rate,  and  this  is  an  undesirable  effect. 

But  more  frequently  in  auricular  fibrillation  digitalis  results 
in  a  condition  in  which,  owing  to  an  area  of  excitability  in  the 
muscle,  each  beat  that  occurs  in  response  to  an  auricular  stimulus 
is  followed  quickly  by  another  beat  which  originates  in  the  ven- 


176          PHARMACOLOGY  AND  THERAPEUTICS 

tricle.  Thus  the  beats  appear  in  pairs  or  couples,  and  make 
"coupled  rhythm."  In  this  the  distance  between  the  members 
of  a  couple  is  fairly  constant,  while  that  between  the  couples  may 
vary  considerably;  and  the  second  beat  of  the  pair  may  or  may 
not  be  palpable  at  the  wrist.  What  is  probably  an  early  stage 
of  coupled  rhythm  is  an  alternation  of  single  beats  with  coupled 
beats.  A  serious  stage  of  it  is  present  when  the  distance  between 
the  couples  is  short,  so  that  the  ventricle  beats  very  rapidly. 
Coupled  rhythm  is  a  common  digitalis  manifestation  in  auricular 
fibrillation,  but  is  sometimes  also  present  with  normal  rhythm, 
every  second  beat  being  a  premature  one. 

Another  digitalis  effect  in  auricular  fibrillation  is  "phasic 
arhythmia,"  which  corresponds  in  general  character  with  that 
arising  from  the  sinus,  but,  so  far  as  known,  has  its  origin  not  at 
the  sinus,  but  in  the  ventricle.  Cohn  has  discovered  that  in 
some  cases  vagus  fibers  pass  directly  to  the  ventricle,  and  it  may 
be  that  phasic  arhythmia  occurs  only  in  such  cases  and  is  a  vagus 
effect. 

E.  The  Coronary  Arteries. — (a)  Constriction  of  the  coronary 
arteries  is  a  real  digitalis  effect,  as  shown  by  perfusion  experi- 
ments. In  the  coronaries  of  young  rabbits  a  solution  of  i  :  20,000 
reduced  the  outflow  from  8  c.c.  per  minute  to  3  c.c.  (Dixon), 
and  by  the  ring  and  strip  methods,  Voegtlin  and  Macht  showed 
contraction  by  both  digitoxin  and  digitalin.  From  therapeutic 
amounts,  this  action  is  probably  negligible,  for,  as  Hatcher 
suggests,  it  seems  improbable  that  the  improvements  in  the 
circulation  from  digitalis  could  occur  if  the  coronaries  were 
constricted. 

In  acute  poisoning,  however,  coronary  constriction  may  be  a 
factor  in  weakening  the  muscle;  and  in  cumulative  poisoning, 
it  may  be  the  cause  of  the  muscular  weakness  which  manifests 
itself  by  alternating  weaker  and  stronger  beats,  the  condition 
known  as  "pulsus  alternans."  This  seems  probable  because 
the  conditions  in  which  pulsus  alternans  not  clue  to  digitalis  is 
observed  are  those  in  which  the  coronary  circulation  is  probably 
inadequate,  viz.,  myocarditis  with  coronary  sclerosis,  the  cardiac 
hypertrophy  of  nephritis,  and  paroxysmal  tachycardia,  (a)  In 
coronary  sclerosis  the  coronary  blood-flow  is  retarded.  (6)  In 
hypertrophy  a  much  larger  blood-supply  than  usual  is  required, 
and  a  time  may  come  when  the  coronary  flow  cannot  meet  the 
needs  of  the  large  mass  of  muscle,  (c)  In  a  rapid  tachycardia  the 
diastolic  pause  is  much  shortened,  and,  as  the  coronary  circula- 
tion goes  on  essentially  during  diastole,  this  shortening  obviously 
causes  a  serious  interference  with  the  cardiac  blood-supply. 


DIGITALIS  177 

Pulsus  alternans  may,  therefore,  be  a  coronary  effect,  and  when  it 
results  from  digitalis,  is  a  decidedly  toxic  one. 

(b)  Nutrition  and  Recuperative  Power. — The  increased  pres- 
sure in  the  aorta  invigorates  the  coronary  circulation,  and  the 
prolonged  diastasis  from  slowing  allows  it  to  last  longer.  At 
the  same  time  the  greater  contraction  in  systole  promotes  the 
emptying  of  the  coronary  veins.  The  result  is  not  only  a  greater 
supply  of  food  and  oxygen  to  the  heart,  to  nourish  it  and  permit 
of  recuperation,  but  also  a  greater  supply  of  the  drug  to  the 
heart  muscle  to  keep  up  its  stimulation. 

Hare  (1897)  nas  shown  how  digitalis  can  improve  the  heart 
nutrition  in  growing  animals,  and,  as  a  result,  probably  the 
general  nutrition.  Of  a  litter  of  10  pigs  two  months  old,  he  kept 
5  as  a  control,  and  treated  the  other  5  with  normal  liquid  digi- 
talis. The  dose  was  2  minims  twice  a  day  for  a  month.  It  was 
then  gradually  increased  until,  at  the  end  of  three  months,  it  was 
10  minims  twice  a  day.  The  food  was  the  same  for  all.  There 
were  no  poisonous  manifestations.  After  four  and  a  half  months 
the  digitalis  pigs  averaged  4  pounds  heavier  than  the  others,  and 
their  hearts  averaged  heavier  by  more  than  ^  ounce  (15  gm.). 
On  examination  by  W.  M.  L.  Coplin  the  ventricular  walls  were 
thicker,  firmer,  and  more  resistant  on  cutting,  and  their  mus- 
cle-fibers measured  0.02  mm.  wider  (average),  i.  e.,  -^  to  ^ 
larger  than  those  of  the  control  pigs. 

Cloetta  (1905)  gave  digitalis  for  several  months  to  adult 
normal  rabbits,  without  effect  upon  the  size  of  the  heart.  Then 
he  artificially  produced  aortic  regurgitation,  keeping  some  of  the 
rabbits  as  controls,  while  to  others  he  gave  digitalis.  The 
hearts  of  the  treated  animals  were  much  more  hypertrophied  and 
more  dilated  than  those  of  the  controls,  and  were  capable  of 
much  greater  stimulation.  Their  aortas  were  also  less  dilated 
than  those  of  the  controls.  These  experiments  would  go  to 
show  that  in  growing  animals  and  in  hearts  that  required  com- 
pensatory hypertrophy  digitalis  might  improve  the  coronary 
circulation  and  the  nutrition  of  the  heart. 

Electrocardiograms,  as  demonstrated  by  Cohn,  Eraser  and 
Jamieson,  show  a  change  under  the  action  of  digitalis  (Fig.  22), 
and  this  effect  has  been  observed  to  persist  for  from  5  to  22  days. 
It  is  not  affected  by  atropine. 

Summary. — Digitalis  may  affect  the  heart  in  regard  to  its  rate 
and  rhythm;  its  tonicity,  contractility,  irritability,  and  conduc- 
tivity; its  nutrition,  oxygenation,  and  recuperation.  Through 
its  action  on  the  vagus  it  may  produce  loss  of  tonicity,  slowing, 
phasic  arhythmia,  momentary  standstill,  or  blocking  of  the  auric- 
ular impulses  in  their  passage  to  the  ventricle.  Through  its  action 


i78 


PHARMACOLOGY    AND    THERAPEUTICS 


on  muscle  it  may  increase  the  tonicity,  the  contractility,  and  the 
irritability,  the  last  to  a  dangerous  degree.  It  makes  a  specific 
change  in  the  electrocardiogram. 

F.  The  Systemic  Arteries. — Besides  its  effect  upon  the  struc- 
tures of  the  heart,  digitalis  in  the  laboratory  may  produce  another 
effect  on  the  circulatory  organs,  viz.,  contraction  of  the  peripheral 
arteries.  The  evidence  of  this  is:  If  a  loop  of  dog's  intestine 
in  situ  is  inclosed  in  an  oncometer  so  that  any  change  in  its  volume 
can  be  measured,  the  administration  of  a  laboratory  dose  of 
digitalis  is  seen  to  be  followed  by  shrinkage  in  the  volume  of  the 
intestine.  The  shrinkage  is  synchronous  with  a  heightened 
general  arterial  pressure,  and  is  due  to  contraction  of  the  vessels. 
If  the  splanchnic  nerves  are  cut  so  as  to  remove  connection  with 


ffi 


Fig.  22. — A.  The  solid  line  represents  the  normal  outline  of  the  electrocar- 
diogram. The  T  wave  is  directed  upward.  The  dotted  line  shows  the  change 
which  occurs  in  the  T  wave  under  the  influence  of  digitalis.  B,  in  a  similar  way, 
shows  the  change  in  certain  cases  when  the  T  wave  is  initially  directed  downward. 
Under  the  influence  of  digitalis  it  turns  upward  (A.  E.  Cohn,  Journal  of  Experi- 
mental Medicine,  June,  1915). 

the  centers,  the  shrinkage  is  less  than  before,  therefore  stimulation 
of  the  vasoconstrictor  center  is  an  effect  of  the  drug. 

Further,  in  perfusion  of  an  isolated  loop  of  intestine  or  of  a 
severed  leg,  i.  c.,  of  organs  removed  from  connection  with  the 
nerve-centers,  if  digitalis  is  added  to  the  perfusing  fluid,  the 
venous  outflow  is  decreased.  This  effect  is  due  to  the  contrac- 
tion of  the  arterioles,  and  shows  that  there  is  a  peripheral  vaso- 
constrictor effect.  The  peripheral  effect  may  be  analyzed — 

(a)  by  the  use  of  apococleine  or  ergotoxine,  two  drugs  which 
paralyze  vasoconstrictor  nerve-endings;  the  digitalis  still  causes 
contraction,  so  must  directly  stimulate  the  arterial  muscle;  and 

(b)  by  perfusion  of  a  coronary  or  pulmonary  artery;  these  con- 
tract under  digitalis,  though  they  have  no  vasoconstrictor  nerves. 
There  is  a  slight  stimulation  of  the  vasoconstrictor  nerve-endings, 


DIGITALIS  179 

but  the  main  peripheral  effect  of  digitalis  is  exerted  on  the  arterial 
muscle.  Thus  digitalis  causes  contraction  of  the  arteries  by  stimu- 
lating the  arterial  muscle  and  the  vasoconstrictor  center,  and  slightly 
by  stimulating  the  vasoconstrictor  nerve-endings. 

The  contraction  of  the  arteries  occurs  mainly  in  the  splanch- 
nic area,  but  ordinarily  occurs  also  in  the  vessels  of  the  limbs. 
After  powerful  doses  the  arteries  of  the  limbs,  as  shown  by  the 
plethysmograph,  may  be  dilated;  for  they  have  less  power  of 
contraction  than  the  splanchnics  and  may  be  forced  into  dilata- 
tion when  the  blood  is  prevented  from  entering  the  splanchnic 
area  (for  it  must  go  somewhere).  The  increased  peripheral 
resistance  in  itself  is  a  resistance  stimulus  to  the  heart,  and,  in 
addition,  promotes  the  coronary  circulation  during  the  diastolic 
pause.  Richards  and  Wood  report  an  increased  production  of 
epinephrine  after  digi toxin  or  strophanthin.  Stewart  and  Scott 
report  that  in  three  cases  of  auricular  fibrillation  the  blood- 
flow  in  the  hands  was  promptly  and  decidedly  increased  by 
digitalis,  this  being  doubtless  a  cardiac  effect.  In  one  case 
with  normal  rhythm  the  blood-flow  in  the  hands  was  slightly 
reduced. 

These  are  the  effects  from  laboratory  doses,  i.  e.,  poisonous 
amounts  administered  intravenously,  and  they  show  the  ten- 
dency of  the  drug.  But  in  practical  therapeutics  the  effect  is  not 
so  striking.  In  fact,  it  is  the  consensus  of  opinion  among  students 
of  the  circulation  that  in  medicinal  doses  digitalis  does  not  cause 
constriction  of  the  arteries  in  measurable  degree. 

Arterial  Pressure. — In  laboratory  animals  digitalis  results  in 
increased  output  of  blood  from  the  heart,  increased  peripheral 
resistance,  and  an  increased  quantity  of  blood  in  the  arteries  at 
the  expense  of  that  in  the  veins.  Hence  we  have  a  decided  rise 
in^arterial  pressure. 

In  man  the  smallness  of  the  dose  and  the  slowness  of  the  drug 
action  permit  the  sensitive  blood-pressure  control  mechanisms 
to  adjust  themselves;  hence  digitalis  in  therapeutic  amounts  may 
cause  no  rise  in  arterial  pressure.  As  Mackenzie  expresses  it, 
"contrary  to  expectation  the  blood-pressure  is  raised  only  in 
exceptional  cases,  even  when  the  drug  is  repeatedly  pushed  until 
full  physiologic  action  is  apparent,  and  even  when  the  patient  is 
evidently  much  benefited  by  the  drug."  Price,  Lawrence,  and 
others  note  similar  absence  of  pressor  changes. 

In  our  own  experience,  a  certain  number  of  heart  cases  have 
shown  decided  improvement  in  arterial  pressure  while  taking 
digitalis;  indeed,  in  a  few  cases  there  has  been  a  very  close  rela- 
tion between  the  amount  of  the  drug  being  taken  and  the  systolic 
pressure.  But  many  other  cases  have  shown  no  effect  at  all 


l8o  PHARMACOLOGY    AND    THERAPEUTICS 

upon  the  pressure,  though  the  appearance  of  poisonous  symp- 
toms demonstrated  that  full  dosage  was  being  given. 

We  have,  therefore,  reached  the  same  conclusion  as  a  number 
of  other  students  of  the  circulation,  viz.,  that  frequently  the 
improvement  in  the  circulation  under  digitalis  cannot  be  fully 
judged  by  estimation  of  the  arterial  pressure.  In  auricular  fibrilla- 
tion arterial  pressure  records  are  worthless,  as  no  two  beats  are 
alike. 

The  Pulmonary  Arteries. — These  tend  to  be  contracted, 
though  the  extent  or  the  significance  of  this  effect  is  not  known. 

The  Cutaneous  Arteries. — The  arteries  of  the  face  and  neck 
tend  to  dilate  and  cause  flushing.  This  seems  to  have  no  appre- 
ciable effect  on  the  general  arterial  pressure,  and  is  not  of  impor- 
tance. It  is  presumably  from  a  central  rather  than  a  peripheral 
action. 

The  Veins. — The  effect  of  digitalis  upon  the  walls  of  the  veins 
is  similar  to  that  upon  the  arteries,  though  it  is  probably  of  no 
therapeutic  significance. 

Kidneys. — The  cardiac  effects  of  digitalis  extend  further  and 
may  be  seen  in  the  action  of  the  kidneys.  With  an  unobstructed 
ureter  a  normal  kidney  will  secrete  more  urine  if  more  blood 
flows  through  it.  And  the  factors  which  affect  the  amount  of 
blood  flowing  through  the  kidney  are:  the  general  arterial  pres- 
sure, the  degree  of  contraction  of  the  kidney  arteries,  and  the 
freedom  of  the  venous  outflow.  Venous  back  pressure,  however 
slight,  or  contraction  of  the  kidney  arterioles,  or  a  fall  in  general 
arterial  pressure,  will  have  a  tendency  to  lessen  the  amount  of 
urine;  while  a  reversal  of  these  conditions  favors  an  increase  in 
the  amount  of  urine. 

As  measured  by  the  oncometer,  the  normal  kidney  of  an 
animal  shrinks  after  a  laboratory  (poisonous)  dose  of  digitalis. 
This  diminution  in  size  is  synchronous  with  the  vasoconstriction 
in  other  parts  of  the  body  and  with  the  rise  in  arterial  pressure, 
hence  it  may  be  assumed  that  the  kidney  arterioles,  in  the  same 
way  as  the  other  arterioles,  are  constricted  by  poisonous  amounts 
of  digitalis.  But  in  human  therapeutics,  as  we  have  seen,  there 
are  presumably  no  essential  constriction  of  arteries  and  no  striking 
rise  in  arterial  pressure.  It  is  a  fact  also  that  the  digitalis  prin- 
ciples apparently  reach  the  kidney  in  such  diluted  form  that,  in 
therapeutic  amounts,  they  have  no  direct  irritant  action  upon  the 
kidney  structures.  Therefore  the  output  of  urine  in  persons 
with  normal  circulation  is  unaffected. 

Hedinger  (1910)  gave  digipuratum  and  digalen  to  rabbits 
intravenously,  and  when  the  kidneys  were  normal,  obtained  a 
slight  increase  in  the  volume  of  the  kidney,  but  a  scarcely  per- 


DIGITALIS  l8l 

ceptible  diuresis.  In  the  early  stages  of  tubular  nephritis  he 
obtained  increase  in  kidney  volume  (dilatation  of  the  arterioles) 
and  a  greater  diuresis.  In  more  severe  tubular  nephritis  and  in 
vascular  nephritis  there  was  no  diuresis.  Jonnescu  and  Loewi 
obtained  a  small  diuretic  effect  from  digitalis  in  normal  animals. 
They  believed  that  the  drug  could  cause  a  local  dilatation  of  the 
kidney  arterioles,  as  do  most  diuretics.  In  cases  with  normal 
rhythm  and  without  edema,  Cohn  emphatically  states  that 
diuresis  does  not  follow  digitalis. 

But  in  cases  with  low  general  arterial  pressure,  venous 
engorgement  and  edema,  i.  e.,  in  persons  with  failing  circulation, 
there  is  regularly  very  little  urine  formed ;  and  in  these  cases  the 
administration  of  digitalis  may  be  followed  by  a  great  increase  of 
the  kidney  excretion.  In  response  to  digitalis,  in  cases  with 
failure  of  the  circulation  we  have  seen  a  urine  output  of  15  or  20 
ounces  a  day  change  to  one  of  100  or  200  ounces,  at  least  for  two 
or  three  days.  So  digitalis  is  diuretic  only  when  it  brings  about 
improvement  in  a  poor  circulation. 

Digitalis  diuresis  is  dependent  upon — (a)  improvement  in  the 
general  circulation,  through  which  accumulated  tissue  fluid 
passes  into  the  blood  to  make  hydremic  plethora,  and  (b)  im- 
provement in  the  kidney  circulation.  It  is  not  due  to  a  direct 
action  of  the  drug  upon  the  kidney  cells.  Consequently  the 
marked  diuresis  lasts  only  until  the  excess  of  fluid  in  the  body 
brought  about  by  venous  stagnation  is  removed. 

The  urine  is  very  dilute  and  poorly  colored  on  account  of  the 
high  proportion  of  water,  but,  at  least  for  the  first  few  days,  con- 
tains an  actual  increase  in  the  total  solids,  and  particularly  in 
the  salts  and  urea.  It  is  probable  that  this  is  due  to  the  washing 
out  of  stored-up  material. 

In  severe  poisoning,  digitalis  may  result  in  the  appearance  of 
albumin  and  blood  in  the  urine.  This  is  due  either  to  a  remote 
local  irritant  action  resulting  in  nephritis,  or  to  excessive  vaso- 
constriction.  Either  of  these  may  also  be  a  cause  of  suppression 
of  the  urine.  (Suppression  is  a  term  to  be  distinguished  from 
retention.  It  signifies  failure  of  the  kidneys  to  secrete  urine, 
while  retention  applies  to  the  bladder,  signifying  failure  of  the 
bladder  to  empty  itself.) 

Venous  Engorgement — Edema  and  Dropsy. — In  cases  with 
failing  circulation  there  is  regularly  some  degree  of  venous  en- 
gorgement, z.  e.,  venous  back  pressure.  And  venous  engorge- 
ment means: 

1.  Increased  general  capillary  transudation.     This  results  in 
increased  formation  of  tissue  fluid. 

2.  Obstruction  to  the  flow  of  lymph;  because  the  lymph- 


I 82  PHARMACOLOGY   AND    THERAPEUTICS 

atics  empty  into  the  veins.     This  checks  the  removal  of  tissue 
fluid. 

3.  Lessened  capillary  absorption  of  tissue  fluid,  because  of 
sluggish  blood-flow. 

4.  A  lessened  amount  of  urine.     This  results  in  lessened 
excretion  of  water. 

The  effect  of  the  combined  action  of  these  factors  is  accumula- 
tion of  fluid  in  the  tissue  spaces  and  serous  cavities  of  the  body, 
i.  e.,  edema  and  dropsy.  There  is  "water  retention"  in  the  body, 
and  the  patient  becomes  water-logged.  Edema  is  a  condition  in 
which  there  is  an  abnormal  amount  of  fluid  in  the  tissue  spaces. 
Dropsy  implies  edema,  but  especially  refers  to  abnormal  collec- 
tions of  transuded  fluid  in  serous  cavities. 

By  improvement  in  the  circulation  digitalis  removes  the 
venous  engorgement.  As  a  result,  the  general  capillary  transuda- 
tion,  i.  e.,  the  formation  of  tissue  fluid,  is  lessened,  while  at  the 
same  time  improved  capillary  absorption  and  a  proper  flow  of 
lymph  remove  the  excess  of  tissue  fluid.  The  result  is  the  reduc- 
tion of  the  amount  of  accumulated  fluid  in  the  tissue  spaces 
and  serous  cavities.  This  fluid  passes  to  the  blood,  swells 
its  volume,  and  makes  a  condition  of  hydremic  plethora.  At 
the  same  time  the  rapidity  of  the  renal  blood-flow  is  increased, 
and  this,  together  with  the  hydremic  plethora,  results  in  diuresis. 
Thus  the  excess  of  fluid  is  removed  from  the  blood  and  eliminated 
from  the  body.  The  ultimate  result  is  the  disappearance  of 
the  dropsy  and  edema,  without  the  loss  to  the  body  of  its  albumin- 
ous elements. 

So  digitalis  tends  to  overcome  dropsy  and  edema,  not  by 
simply  removing  the  accumulated  blood  from  the  veins  into  the 
arteries,  nor  by  directly  stimulating  the  kidneys,  but — (i)  By 
lessening  general  capillary  transudation;  (2)  by  increasing  the 
lymph-flow  and  promoting  capillary  absorption,  and  (3)  by 
increasing  the  excretion  of  urine.  All  these  depend  upon  its 
power  to  activate  the  circulation;  or,  in  other  words,  its  power  to 
lessen  venous  engorgement. 

The  early  stages  of  edema  are  not  always  obvious,  for  a 
human  being  can  store  a  great  amount  of  liquid  beyond  the  nor- 
mal before  edema  begins  to  show.  But  a  greater  or  less  degree 
of  water-logging  or  water-storage  is  a  regular  accompaniment  of 
a  failing  heart,  so  that  even  when  the  edema  is  not  apparent, 
digitalis  may  prove  diuretic. 

Digitalis  is  of  no  value  as  a  diuretic  in  the  removal  of  serous 
exudations  due  to  inflammatory  or  local  causes,  as  in  cirrhosis 
of  the  liver,  peritonitis,  etc.,  unless  these  are  accompanied  by 
circulatory  inefficiency. 


DIGITALIS  183 

Value  of  Digitalis. — We  might  sum  up  the  theoretically  valu- 
able effects  of  digitalis  in  a  failing  circulation  as  follows : 

1.  On  the  heart:  (a)  Slowing,     (b)  Increased  contractility. 
(c)  Increased  tonicity.   (d)  Improved  nutrition,     (e)  In  auric- 
ular fibrillation,  slowing  and  steadying  of  the  ventricular  rhythm. 

2.  On  the  blood — improved  oxidation  from  improved  pulmo- 
nary blood-flow. 

3.  In  venous  accumulation — the  removal  of  edema  and  dropsy. 
Respiratory  System.— Therapeutic  doses  have  little  direct 

influence  on  respiration,  but  they  may  stimulate  the  respiratory 
center  through  the  improvement  in  the  cerebral  circulation; 
or  may  help  the  lungs  through  removal  of  congestion  or  edema. 
Poisonous  doses  stimulate  the  respiratory  center  so  that  the 
respiration  becomes  strong  and  deep.  With  the  fall  in  arterial 
pressure  in  the  late  stages  of  poisoning  the  respiratory  center  fails. 

Nervous  System. — The  brain  may  be  affected  through  its 
increased  blood-supply.  There  is  no  direct  action  except  upon 
the  centers  of  the  medulla.  The  chief  constantly  acting  medul- 
lary centers  are  the  vagus,  the  vasoconstrictor,  and  the  respira- 
tory, and  in  this  sequence  these  are  stimulated  by  the  drug.  If 
poisonous  doses  are  administered,  these  centers  are  eventually 
depressed.  Other  centers  sometimes  affected  by  digitalis  are 
the  heat-regulating,  so  that  temperature  in  fever  tends  to  be 
lowered,  the  vomiting,  and  the  convulsive,  which  may  be  the 
cause  of  convulsions  in  the  late  stages  of  poisoning.  The  nerve- 
endings  which  are  stimulated  are  those  of  the  vagus  and  vaso- 
constrictor nerves. 

Elimination. — The  active  principles  are  excreted  partly  by 
the  kidneys  and  partly  by  the  intestines.  Their  excretion  is 
slow,  so  that  continued  administration  of  large  doses  may  give 
rise  to  cumulative  poisoning.  And  the  administration  of  a  full 
intravenous  dose  of  one  of  the  active  principles  of  the  group 
during  or  following  shortly  after  a  course  of  digitalis  by  mouth 
has,  in  a  number  of  instances,  resulted  fatally.  This  last  state- 
ment is  particularly  true  of  strophanthin,  which  has  been  the 
principle  of  choice  for  intravenous  use. 

The  Digitalis  Allies. — Strophanthus  would  seem  to  be  ab- 
sorbed from  the  alimentary  tract  with  less  rapidity  and  more 
uncertainty  than  digitalis  (Hatcher).  It  is  at  least  50  times  as 
poisonous  to  the  heart  muscle  (Haynes,  Edmunds,  Houghton). 

Either  strophanthin  of  the  Pharmacopoeia,  or  ouaba'in  (crystal- 
line grains  strophanthin),  may  be  dissolved  in  salt  solution  and 
given  by  deep  intramuscular  injection  or  intravenously.  When 
^V  grain  (i  mg.),  the  maximum  dose,  is  passed  into  a  vein  of  a 
human  being,  it  may  show  its  results  in  slowing  of  the  pulse  in 


184  PHARMACOLOGY    AND    THERAPEUTICS 

from  one-half  to  one  hour,  with  strengthening  of  the  heart. 
Provided  that  digitalis  has  not  already  been  given,  this  treatment 
may  be  employed  when  the  symptoms  of  the  cardiac  weakness 
are  very  severe,  and  particularly  if  there  is  auricular  fibrillation. 

Strophanthin  is  said  to  be  eliminated  much  more  rapidly  by 
the  kidneys  than  the  digitalis  glucosides,  so  that  cumulative 
poisoning  does  not  occur.  To  test  this  Frankel  gave  submaximal 
doses  to  a  cat  for  ninety-two  days  and  got  no  symptoms  of  over- 
dosage;  Hatcher's  work  corroborates  this.  In  poisoning,  there 
is  no  striking  constriction  of  the  systemic  arteries;  and  Dixon 
has  shown  by  a  perfusion  experiment  that  while  one  part  of  the 
tincture  of  digitalis  in  2500  was  sufficient  to  constrict  strongly 
the  coronary  arteries  of  a  rabbit,  a  similar  strength  of  the  tincture 
of  strophanthus  had  no  effect.  In  a  number  of  cases  the  ap- 
pearance of  diarrhea  is  a  bar  to  the  use  of  strophanthus,  and 
this  is  attributed  to  a  direct  action  of  strophanthin  on  the  in- 
testinal muscles. 

Two  things  in  the  action  of  strophanthus  must  be  especially 
noted,  first,  its  smaller  power  to  relieve  conditions  due  to  failure 
of  compensation,  except  when  used  intravenously;  and,  second, 
its  great  toxicity  to  the  muscle  of  the  heart. 

Convallaria  has  no  advantages  over  digitalis  and  is  more  toxic. 

Hellebore'in,  dose,  \  grain  (0.03  gm.),  has  been  found  ex- 
perimentally to  have  muscular  effects  similar  to  those  of  digi- 
talis, but  without  its  vagus  effects.  Its  application  in  thera- 
peutics has  not  been  determined. 

Toxicology. — /.  Poisoning  from  an  overwhelming  dose,  as  of 
i  mg.  of  strophanthin  per  kilo  intravenously  in  a  dog,  produces  a 
regular  sequence  of  effects  in  four  well-defined  stages,  with  death 
in  a  few  minutes.  (See  Plate  I.)  The  stages  are:  (i)  Vagus 
and  vasoconstrictor  stimulation,  with  slowed  heart  and  rapid  rise 
in  blood-pressure,  the  diastolic  relaxation  indicating  diminished 
tone.  (2)  Vagus  action  predominating  with  greater  loss  of  tone 
and  heart-block,  or  short  periods  of  vagus  standstill,  and  some- 
times premature  beats  from  muscular  stimulation.  (3)  Muscular 
action  predominating,  with  abrupt  change  to  tachycardia,  the 
ventricle  beating  at  a  very  rapid  rate  and  usually  not  in  unison 
with  the  auricle;  arterial  pressure  very  high.  (4)  Muscular 
weakness  with  excessive  irritability,  auricle  fibrillating;  ventricle 
losing  contractility  passes  into  fibrillation  and  death  takes  place. 
The  heart  is  usually  found  in  a  state  of  relaxation,  but  Eckler 
(1912)  reports  that  as  many  as  12  out  of  62  mammal  hearts  were 
found  in  systolic  contraction  after  deaths  from  ouabain,  strophan- 
thus, and  digitalis.  Hatcher  has  had  death  occur  in  cats  during 
the  intravenous  administration;  and  in  a  patient  in  one  of  the 


DIGITALIS  185 

New  York  hospitals,  death  occurred  three  minutes  after  an 
intravenous  dose. 

2.  Poisoning  From  a  Single  Large  Dose  Taken  by  Mouth.— 
This  is  a  very  rare  event.  Any  one  of  the  actions  upon  the  heart, 
as  outlined  above,  may  manifest  itself.  Excessive  vagus  action 
may  show  in  pronounced  slowing,  sinus  arhythmia,  periods  of 
momentary  cardiac  standstill,  or  some  degree  of  heart-block. 
Excessive  irritability  may  show  in  premature  beats,  auricular 


Fig.  23. — Digitalis  poisoning  in  dog,  showing  intermittent  heart-block.     Upper 
tracing,  auricle;  lower,  ventricle.     The  down-stroke  is  systole. 

fibrillation,  or  paroxysmal  tachycardia.  In  addition,  there  may 
be  nausea,  vomiting,  and  diarrhea;  discomfort  about  the  heart, 
coming  on  early;  deep,  slow  respiration,  or,  in  late  stages,  dysp- 
nea; general  muscular  weakness  with  prostration.  At  a  late 
stage  the  urine  may  be  albuminous  or  bloody,  or  may  be  sup- 
pressed, and  there  may  be  convulsions  which  are  due  either  to 
the  asphyxia  or  to  stimulation  of  the  convulsive  centers.  Death 
takes  place  with  failure  of  the  respiration,  following  collapse. 
But  the  death  occurs  in  spite  of  artificial  respiration,  and  is  due 


l86          PHARMACOLOGY  AND  THERAPEUTICS 

to  failure  of  the  circulation  from  ventricular  fibrillation,  which 
in  mammals  usually  takes  the  place  of  the  continued  systole 
of  cold-blooded  animals. 

We  have  had  reported  to  us  one  such  death  from  the  intra- 
venous administration  of  digitalis  in  a  human  being,  and  many 
deaths  following  the  intravenous  use  of  ^3  grain  (i  mg.)  of 
strophanthin,  death  resulting  in  from  three  minutes  to  about 
an  hour.  Serious  symptoms  have  also  been  reported  from  -^ 
grain  of  digi toxin.  These  deaths  have  regularly  occurred  in 
patients  who  had  been  taking  digitalis  for  several  days  previously. 

3.  Cumulative  Poisoning. — This  comes  from  the  use  of  the 
drug  in  medicine.  The  signs  of  overdosage  in  the  medicinal 
administration  of  digitalis  should  be  recognized  as  soon  as  pos- 
sible, for  such  poisoning  is  common  in  hospital  and  private  prac- 
tice, and  its  manifestations  are  not  infrequently  misinterpreted 
as  symptoms  of  the  heart  disease.  But  there  are  a  number  of 
cases  in  which  we  may  be  unable  to  say  with  certainty  that 
digitalis  is  the  cause,  until  we  note  the  disappearance  of  the  mani- 
festation shortly  after  the  digitalis  is  stopped,  and  its  reappear- 
ance under  further  administration  of  the  drug. 

MANIFESTATIONS  OF   OVERDOSAGE   OF   DIGITALIS 

I.  SUBJECTIVE  MANIFESTATIONS: 

a.  Loss  of  appetite,  nausea,  vomiting,  diarrhea. 

b.  Oppression  about  heart,  palpitation,   tachycardia,  con- 

sciousness of  premature  or  skipped  beats. 

c.  Headache. 

II.  OBJECTIVE  MANIFESTATIONS: 

a.  Effect  on  sinus  node — 

1.  Excessive  slowing. 

2.  Sinus  arhythmia/  Exaggerated  respiratory. 

|  Non-respiratory. 
f  Prolonged     auriculoventricular     in- 

7     77 a    .  j       ,,    i      terval  (incipient  block). 

b.  bttect  on  a-v  bundle  i  ^    ,.  ,  ,  ,     ,     ,    .,, 

^  ,         ,      rartial  or  complete  block   (with  or 

or  Tawara  s  node  ,  ,      \         ,.  ^ 

without  bradycardia). 

Nodal  rhythm. 

,  Premature  beats  (extrasystoles). 
.  Paroxysmal  tachycardia. 

c.  Effect  on  muscle—     i  3.  Nodal  and  retrograde  rhythms. 

Overexcitability  |  4.  Auricular  flutter. 

5.  Auricular  fibrillation. 

6.  Ventricular  fibrillation. 


DIGITALIS  187 

d.  Combined  effects  on  a-v  bundle  and  on  muscle — 

(  i.  Complete      heart-block, 
but  little  or  no  brady- 


In  auricular  fibrillation  • 


cardia. 


2.  Coupled  rhythm. 

3.  Phasic  arhythmia. 

2.  In  normal  rhythm — complete  block  without  brady- 

cardia  (owing  to  increased  excitability). 
e.  Constriction  of  coronary  arteries — a  possible  influence — 

pulsus  alternans. 
These  have  all  been  explained  in  detail  above. 

In  this  connection  the  possibility  of  persistence  of  effect 
must  be  kept  in  mind,  for,  as  ascertained  by  Hatcher  in  cats, 
the  drug  action  may  continue  in  some  cases  for  as  much  as  three 
weeks  or  a  month  after  a  single  intravenous  dose.  I  have  ob- 
served persistence  of  partial  heart-block  for  three  and  one-half 
weeks  after  the  stoppage  of  digitalis,  and  of  complete  block  for  at 
least  one  week.  Conn's  electrocardiographic  tracings  have  shown 
a  digitalis  effect  in  man  as  late  as  twenty-two  days  after  the  drug 
was  stopped.  Cushny  reports  a  case  of  auricular  fibrillation  in 
which,  through  the  influence  of  digitalis,  "inhibition  had  gained 
a  permanent  control  over  the  heart,"  so  that  the  effect  persisted 
indefinitely  after  the  drug  was  stopped,  or  was  perpetuated  by 
an  occasional  dose.  From  my  clinical  experience  I  .should 
judge  that  such  an  effect  in  auricular  fibrillation  is  not  uncommon. 
Except  when  it  is  administered  intravenously,  the  margin  of 
safety  with  digitalis  is  a  large  one,  so  that  there  is  no  undue  danger 
in  the  use  of  even  large  doses  by  mouth  or  hypodermatically,  if 
the  administration  is  stopped  when  one  of  the  following  condi- 
tions arises,  viz. : 
/.  Nausea  becomes  marked. 

2.  The  radial  pulse  goes  below  60.  The  pulse  may  become  pro- 
gressively slower  for  a  few  days  after  the  drug  is  stopped, 
hence  the  necessity  for  ceasing  its  administration'before  the 
slowing  has  become  extreme. 

j.  A  rapid  ventricle  with  rate  unaffected  by  digitalis  for  several 
days  suddenly  becomes  slower  (heart-block). 

4.  A  regular  ventricular  rhythm  changes  to  irregular,  as  from  pre- 

mature beats  or  the  development  of  auricular  fibrillation;  or 
becomes  intermittent,  as  from  partial  heart-block. 

5.  Paroxysmal  tachycardia  occurs. 

6.  The  absolutely  irregular  rhythm  of  auricular  fibrillation  becomes 

slow  and  regular  (complete  heart-block),  or  shows  coupled 
rhythm  or  phasic  arhythmia. 


1 88  PHARMACOLOGY   AND    THERAPEUTICS 

A  considerable  risk  may  be  avoided  by  refraining  from  the  use 
of  digitalis — (a)  When  the  ventricle  is  intermitting;  (b)  when 
there  are  premature  beats;  or  (c)  when  there  is  bradycardia. 

Clinical  reports  of  fatalities  have  borne  out  Hatcher's  findings 
that  an  intravenous  dose  of  any  one  of  the  principles  of  the  group 
is  much  more  active  if  digitalis  has  previously  been  administered 
by  mouth  or  hypodermatically.  For,  as  Hatcher  reports,  even 
as  late  as  a  month  after  the  intravenous  injection  in  a  cat  of  a 
nearly  fatal  dose  of  digitalis,  the  test  animal  may  require  a 
smaller  intravenous  dose  for  lethal  effect  than  an  animal  that 
has  had  no  digitalis. 

Treatment. — In  the  simplest  condition  of  poisoning,  when 
excessive  slowing  or  irregularity  or  intermittence  of  the  heart,  or 
tachycardia,  begins  to  show,  the  treatment  is  simply  to  stop  the 
drug  and  keep  the  patient  quiet  in  bed  until  the  effect  of  the  drug 
has  worn  off.  To  check  excessive  vagus  action,  atropine  sul- 
phate, ^Vgram  (o.ooi  gm.),  may  be  employed  hypodermatic- 
ally,  but  its  effect  lasts  not  over  an  hour.  For  excessive  irri- 
tability, sodium  bromide,  i  to  2  drams  (4-8  gm.),  morphine 
sulphate,  |  grain  (0.015  gm.),  and  a  hot-water  bag  or  ice-bag 
over  the  heart  may  give  some  relief.  In  severe  poisoning  there 
must  be  absolute  repose  and  freedom  from  exertion  for  several 
days,  the  mere  effort  of  sitting  up  in  bed  being  sufficient  in  some 
cases  to  precipitate  failure  of  the  circulation  and  death.  If 
necessary,  body  warmth  must  be  maintained  by  blankets,  hot- 
water  bottles,  etc.  Symptoms  are  treated  as  they  arise,  there 
being  no  specific  treatment. 

So  far  as  conduction  is  concerned,  there  is  some  evidence  that 
caffeine  tends  to  antagonize  digitalis,  hence  it  may  prove  a  good 
drug  in  heart-block.  On  several  occasions  I  have  seen  caffeine 
apparently  undo  the  work  of  digitalis  in  auricular  fibrillation, 
an  observation  confirmed  by  Barton. 

Therapeutics. — From  our  studies,  it  is  evident  that  the  only 
use  for  digitalis  in  therapeutics  is  to  modify  the  action  of  the 
heart.  And  it  is  to  be  employed  neither  to  constrict  the  arte- 
ries nor  to  act  directly  upon  the  kidneys.  It  is  also  evident 
that  among  the  cardiac  disturbances  which  require  treatment 
there  are  those  in  which  digitalis  has  a  great  value,  those  in  which 
it  has  a  small  value,  those  in  which  it  has  no  value  at  all,  and  those 
in  which  it  is  distinctly  harmful  or  even  dangerous.  Discrimina- 
tion, therefore,  is  most  essential  in  the  use  of  this  powerful 
remedy. 

We  learn  further  that  the  determining  factor  in  our  choice 
of  digitalis  as  the  drug  to  use  is  not  the  state  of  the  valves,  but 
rather  the  functional  condition  of  the  various  parts  of  the  cardiac 


DIGITALIS  189 

mechanism.  According  to  Lewis,  the  relative  frequency  of 
disorders  of  the  cardiac  mechanism  in  hospital  cases  would  ap- 
proximate as  follows:  Heart-block,  5  per  cent.;  sinus  arhythmia, 
5  per  cent.;  pulsus  alternans,  5  per  cent.;  paroxysmal  tachy- 
cardia including  auricular  flutter,  10  per  cent.;  premature  con- 
tractions, 34  per  cent.;  auricular  fibrillation,  41  per  cent.  The 
role  of  digitalis  in  these  several  conditions  is  as  follows: 

Heart-block. — In  incipient  or  partial  heart-block  digitalis  is 
contraindicated,  for  it  tends  to  increase  the  degree  of  block.  In 
complete  block  it  has  been  recommended  by  Bachmann  and 
others  on  the  ground  that  it  tends  to  bring  the  auricular  and 
ventricular  rates  more  nearly  together,  by  slowing  the  rate  of 
the  auricle  and  increasing  that  of  the  ventricle;  but  in  the  only 
one  of  my  cases  in  which  it  had  any  effect  (see  case  report  under 
Auriculoventricular  Bundle,  p.  173)  it  brought  the  auricle  and 
ventricle  to  the  same  rate,  but  in  "reversed  rhythm,"  the  auricle 
following  the  ventricle  instead  of  preceding  it;  and  this  was 
harmful. 

Sinus  Arhythmia. — In  this  condition  digitalis  is  useless  and 
probably  harmful.  These  hearts  do  best  when  treated  by  other 
measures  than  drugs. 

Pulsus  Alternans.- — In  this  weakened  state  digitalis  may  at 
times  be  of  some  value,  but  its  effects  are  problematic,  and  at 
least  in  some  cases  are  harmful.  Especially  is  this  true  of  the 
myocarditis  cases  with  coronary  sclerosis. 

Paroxysmal  Tachycardia. — As  this  is  a  peculiar  action  of  the 
heart,  coming  on  with  great  suddenness  and  ceasing  just  as 
abruptly,  and  lasting  from  a  fraction  of  a  minute  even  to  months, 
it  is  difficult  to  say  whether  any  drug  given  is  effective  or  not. 
Some  cases  cease  soon  after  the  commencement  of  digitalis  and 
some  do  not.  Where  the  beats  arise  at  the  sinus  node  or  in  the 
auricle,  digitalis  might  be  expected  to  be  of  value  by  retarding 
conduction,  but  when  the  beats  arise  in  the  ventricle,  it  can  only 
be  harmful. 

In  auricular  flutter,  a  condition  characterized  by  an  extremely 
rapid  auricular  contraction,  rate  above  300,  usually  with  ven- 
tricle beating  at  the  same  rate  or  half  the  rate,  digitalis  may 
change  the  flutter  to  fibrillation,  and  this  seems  to  act  by 
submerging  the  original  fast  rhythm  and  eventually  restoring 
the  rhythm  to  normal.  Even  if  it  does  not  do  this,  digitalis 
will  be  of  value  by  establishing  some  degree  of  block  (Thomas 
Lewis) . 

Premature  Contractions. — Though  a  few  cases  have  been 
reported  of  the  disappearance  of  premature  contractions  during 
the  administration  of  digitalis,  it  is  certain  that  in  most  cases 


1 90          PHARMACOLOGY  AND  THERAPEUTICS 

digitalis  has  a  decided  tendency  to  increase  these  indications  of 
irritability. 

Auricular  Fibrillation. — It  is  in  auricular  fibrillation,  above 
all  other  cases,  in  -which  there  is  an  almost  ideal  effect  from  digi- 
talis; in  fact,  the  results  of  digitalis  are  dramatic.  Lewis  says  that 
"in  hospital  practice,  of  those  with  obvious  cardiac  failure 
at  least  60  per  cent,  have  auricular  fibrillation."  Large  doses 
should  be  given  at  the  outset,  and  if  the  fibrillation  is  permanent, 
should  be  followed  by  smaller  doses  once  or  twice  a  week  or  once 
a  day,  for  months,  or  even  throughout  the  life  of  the  patient. 
The  action  of  the  drug  is  not  to  overcome  the  fibrillation,  though 
a  slowing  in  the  rate  of  fibrillation  has  been  noted  (Cushny); 
but,  so  far  as  we  know,  it  is  to  impair  the  conductivity  of  the 
auriculoventricular  bundle,  i,  e.,  to  establish  a  partial  heart- 
block.  The  result  is  that  impulses  from  the  auricle  get  through 
to  the  ventricle  only  at  longer  intervals,  and,  as  a  consequence, 
the  ventricle  becomes  more  nearly  regular,  is  less  rapid,  and  has 
greatly  increased  power.  The  production  of  complete  block, 
shown  by  the  regularity  of  the  pulse,  should  be  avoided;  if  it 
occurs,  it  is  an  indication  for  immediate  reduction  of  the  dose. 

In  a  case  of  auricular  fibrillation,  if  the  condition  is  imme- 
diately serious,  an  intravenous  injection  of  digipuratum,  i^ 
grains  (o.i  gm.),  or  of  strophanthin  T£n  to  ^  grain  (0.0005- 
o.ooi  gm.),  may  be  employed.  But  usually  it  suffices  to  give 
15-30  minims  (1-2  c.c.)  of  the  tincture  three  or  four  times  a 
day,  or  a  corresponding  amount  of  the  powdered  leaves,  i.  e., 
I2~3  grains  (0.1-0.2  gm.),  or  of  the  infusion,  i.  e.,  1^-3  drams 
(6-12  c.c.). 

It  is  to  be  noted  that  frequently  the  infusion  is  given  in  larger 
proportional  dosage  than  other  preparations.  Doses  of  § 
ounce  (15  c.c.)  are  not  unusual,  and  this  dose  is  made  from  the 
same  amount  of  digitalis  as  36  minims  (2.4  c.c.)  of  the  tincture. 
Yet  such  a  dose  of  the  tincture  is  seldom  employed.  This  is 
perhaps  the  reason  why  some  thoughtlessly  consider  the  in- 
fusion the  better  preparation. 

The  table  on  p.  191,  giving  the  effects  of  digitalis  as  recorded 
by  Mackenzie  in  a  case  of  mitral  stenosis  with  auricular  fibrilla- 
tion, is  typical.  The  B.  P.  tincture  was  used  by  Mackenzie.  Its 
equivalent  in  U.  S.  P.  tincture  is  expressed  in  the  table. 

In  cases  in  which  great  excitability  shows  by  varying  periods 
of  auricular  fibrillation,  paroxysmal  tachycardia,  and  premature 
ventricular  beats,  digitalis  is  much  less  certain  than  in  simple 
auricular  fibrillation.  P'or  only  such  beats  as  have  their  origin 
in  the  auricle,  and  consequently  are  affected  by  depression  of 
conductivity,  will  be  favorably  modified  by  digitalis;  while 


DIGITALIS 


DATE. 

TINCT.  DIGITALIS, 
U.  S.  P. 

PULSE-RATE. 

Oz.  OF  URINE. 

REMARKS. 

July  6 

1  06 

27 

8 

9 
10 
ii 

12 

13 
14 

37K  minims 

II2#           " 

ii2#      <f 

II2# 

II2>£           " 

75 

no 

73 
70 
72 
72 
60 
68 

41 
29 

37 
52 
63 
42 
16 

Headache 
Headache;  nausea 
Vomited'  headache 

1C 

t>7 

14 

Vomited'  headache 

16 

63 

27 

Better'  no  vomiting 

17 

CO 

16 

18 

70 

•2Q 

19 

60 

26 

20 

70 

3O 

21 

78 

C7 

Breathing  much  easier 

those  arising  in  the  ventricle  itself  may  be  made  worse  by  the 
increase  of  excitability.  I  have  seen  several  of  these  cases.  In 
some,  digitalis  gave  good  results;  in  others  it  did  no  apparent 
good  or  harm. 

Normal  Rhythm. — In  the  cases  in  which  the  heart  is  beating  in 
normal  rhythm  and  is  regular,  but  rapid  and  weak,  it  is  quite 
customary  to  employ  digitalis  with  the  dual  purpose  of  slowing 
the  heart  and  strengthening  its  beat.  And  it  is  in  these  cases,  in 
which  we  desire  and  might  expect  so  much,  that  we  often  meet 
with  disappointment.  At  times  the  drug  seems  utterly  lacking 
in  power  to  check  the  rate  or  to  add  to  the  strength  of  the  heart, 
even  though,  as  shown  by  the  development  of  toxic  effects,  the 
digitalis  is  given  beyond  the  physiologic  limit.  This  may  be 
due  either  to  an  affection  of  the  muscle  caused  by  failure  of 
nutrition  or  the  toxins  of  the  disease,  or  to  reflexes  of  which  we  do 
not  know  the  nature. 

Use  in  High  Arterial  Pressure. — In  this  condition  the  ques- 
tion may  arise  as  to  the  advisability  of  employing  digitalis.  As 
the  doses  administered  in  therapeutics  do  not  have  a  strong 
tendency  to  raise  arterial  pressure,  high  pressure  is  not  of  itself 
a  contraindication  to  the  employment  of  the  drug.  The  author 
has  seen  a  number  of  cases  with  tension  between  200  and  260,  in 
which  the  pressure  fell  during  digitalis  administration. 

Use  as  Determined  by  Rhythm  and  Rate. — The  rhythm  serves 
merely  to  determine  the  functional  condition.  The  most  met 
with  rhythms,  with  their  probable  significance  as  judged  by  rate, 
are  as  follows : 

i.   Ventricle  regular  in  frequency — 

(a)  Pulse  55  to  140 — normal  rhythm — if  rapid,  try  digitalis, 
but  watch  for  toxic  manifestations. 


IQ2  PHARMACOLOGY   AND    THERAPEUTICS 

(b)  Pulse  below  55 — heart-block? — avoid  digitalis. 

(c)  Pulse  above  140 — paroxysmal  tachycardia,  auricular  flut- 
ter— try  digitalis. 

(d)  Pulse    alternating   weaker   and    stronger    beats — pulsus 
alternans — try  digitalis. 

2.  Ventricle  showing  regular  waxing  and  waning  of  the  rate 
independently  of  respiration — sinus  arhythmia— avoid  digitalis. 

3.  Ventricle  showing  premature  or  abortive  beats — avoid  digi- 
talis. 

4.  Ventricle  beating  in  couples — avoid  digitalis. 

5.  Ventricle  regularly  intermittent — partial  heart-block — avoid 
digitalis. 

6.  Ventricle  persistently  irregular  and  disorderly — auricular 
fibrillation- — use  digitalis  in  large  doses. 

The  Influence  of  Conditions  of  the  Heart  and  Arteries  on 
the  Usefulness  of  the  Drug. — (a)  In  Simple  Muscular  Inability 
Without  Valvular  Lesion. 

Simple  dilatation.  In  this  the  muscle  has  lost  its  tone  and 
become  abnormally  relaxed,  and  its  contraction  is  weak;  in  addi- 
tion, there  may  be  a  systolic  leakage  through  the  mitral  valves, 
not  due  to  valvular  disease,  but  to  the  dilatation  of  the  mitral 
orifice  and  the  loss  of  tone  of  the  papillary  muscles.  Digitalis 
tends  to  make  the  systole  stronger  and  more  complete,  and,  by 
restoring  the  tone,  prevents  the  abnormal  diastolic  relaxation 
and  weakness.  At  the  same  time  the  mitral  ring  contracts  to 
normal  again  and  the  papillary  muscles  are  toned,  so  that  the 
relative  insufficiency  of  the  mitral  valves  disappears.  The 
result  is  an  efficient  circulation.  In  the  moderate  dilatation  of 
acute  febrile  diseases  digitalis  may  be  ineffective  because  of  the 
toxic  action  of  the  bacterial  products. 

Chronic  myocarditis  and  fatty  degeneration.  In  these  a 
portion  of  the  muscle  substance  is  changed  and  replaced  by  non- 
contractile  tissue  (connective  tissue  in  myocarditis;  fat  in  fatty 
degeneration),  so  that  the  drug  has  less  muscle  substance  to 
stimulate  by  direct  action.  In  some  of  these  cases,  too,  there  is 
impairment  of  the  coronary  circulation  by  coronary  sclerosis;  and 
in  some  the  slowing  of  the  heart  takes  place  without  a  correspond- 
ing increase  in  ventricular  strength,  so  that  the  output  is  actu- 
ally lessened  instead  of  increased.  Because  of  these  things, 
therefore,  digitalis  may  be  contraindicated,  or  at  least  must  be 
used  with  caution. 

In  acute  toxic  myocarditis,  as  in  the  infectious  febrile  diseases, 
digitalis  may  fail  either  to  slow  or  to  strengthen  the  heart.  In 
most  cases,  however,  it  is  effective. 

(b)  Muscular  Inability  Associated  with  a  Valvular  Lesion.— 


DIGITALIS  193 

The  common  valvular  defects  are  those  of  the  left  heart,  and 
they  either  make  a  valve  inefficient  so  as  to  permit  backward 
leakage  or  regurgitation,  or  cause  a  narrowing  or  stenosis  of  the 
valvular  orifice  so  as  to  obstruct  the  onward  passage  of  the  blood. 
The  common  valvular  lesions  which  allow  regurgitation  of  blood 
are  mitral  insufficiency  and  aortic  insufficiency.  The  common 
lesions  which  cause  obstruction  to  the  passage  of  blood  are 
mitral  stenosis  and  aortic  stenosis. 

In  mitral  insufficiency  there  is  a  systolic  regurgitation  of  blood 
from  the  ventricle  into  the  auricle  through  the  insufficient  mitral 
valve.  This  leakage  is  ordinarily  compensated  for  by  enlarge- 
ment of  the  ventricular  cavity  and  hypertrophy  of  the  heart 
muscle.  When  the  muscle  fails,  there  is  a  condition  of  flabby 
heart  wall  and  papillary  muscles,  with  relaxed  mitral  orifice, 
resembling  that  in  simple  dilatation,  but  with  a  permanent 
mitral  leak.  In  this  condition  digitalis  may  prove  valuable. 

In  aortic  insufficiency  there  is  a  diastolic  regurgitation  from 
the  aorta  through  the  insufficient  aortic  valves  back  into  the 
ventricle.  In  this  condition  the  left  ventricle  is  usually  very 
large  and  its  capacity  enormously  increased.  In  the  arterio- 
sderotic  type  the  aorta  is  impaired,  there  is  usually  more  or  less 
myocarditis  and  general  arteriosclerosis,  and  the  failure  of  the 
sclerosed  coronaries  to  meet  the  needs  of  the  very  large  heart  is 
probable.  Hence  digitalis  should  be  used  with  caution.  In 
the  endocarditic  type  the  dilatation  and  hypertrophy  of  the 
ventricle  through  the  natural  compensatory  changes  are  regularly 
very  marked,  the  heart  is  enormous,  and  there  is  a  very  great 
output  of  blood  at  each  systole.  This  factor  and  the  prompt 
leakage  are  enough  to  make  a  great  difference  between  the  systolic 
and  diastolic  aortic  pressures,  hence  a  sudden  great  distention  of 
the  aorta  in  systole,  a  matter  of  importance  if  there  is  aortic 
disease.  In  such  a  case  the  prolongation  of  diastole  by  digitalis 
does  not  seem  to  make  any  serious  difference  so  far  as  the  leakage 
is  concerned  (Stewart),  and  it  allows  a  longer  time  for  the  addi- 
tional coronary  blood-supply  needed  by  the  greatly  hyper- 
trophied  wall  of  the  heart. 

The  peripheral  pressure,  however,  is  not  influenced  so  much 
by  the  size  of  the  leak  as  by  reflexes  through  the  depressor  nerve 
which  in  man  runs  afferently  in  the  vagus  from  the  heart  or  from 
the  adjoining  portion  of  the  aorta.  When  the  intra-aortic  pres- 
sure is  abnormally  high,  this  nerve  carries  impulses  which  result 
in  a  reflex  dilatation  of  the  peripheral  arterioles.  So  in  aortic 
insufficiency,  either  because  of  the  very  high  aortic  systolic 
pressure  or  the  sudden  overdilatation  of  the  aorta  from  the  great 
output  at  a  single  beat,  depressor  impulses  are  set  going;  and. 
13 


IQ4  PHARMACOLOGY    AND    THERAPEUTICS 

there  is  immediately  a  reflex  dilatation  of  the  arterioles,  which 
causes  greatly  lessened  peripheral  resistance  and  low  diastolic 
pressure.  Whether  or  not  digitalis,  through  its  effect  upon  the 
vasoconstrictor  mechanism,  may  counteract  this  depressor 
reflex,  which  is  protective  by  letting  off  at  the  periphery  the  exces- 
sive pressure  caused  by  the  great  output  in  systole,  is  a  question. 
If  it  does  so,  it  may  be  harmful. 

In  mitral  stenosis  the  mitral  orifice  is  narrowed  by  thickening 
of  the  valves  or  their  adherence  together  so  as  to  obstruct  the 
filling  of  the  ventricle  from  the  auricle.  The  natural  compensa- 
tion in  this  case  is  secured  through  hypertrophy  and  dilatation 
of  the  left  auricle  and  of  the  right  ventricle,  so  that,  by  added 
pressure,  the  proper  amount  of  blood  is  forced  through  the  nar- 
rowed aperture.  Under  digitalis,  on  the  one  hand,  the  filling  of 
the  left  ventricle  through  this  narrowed  orifice  is  favored  by  a 
lengthened  diastole  (and  the  strengthening  of  the  left  auricle  and 
right  ventricle),  and  this  has  a  slight  tendency  to  improve  the 
systemic  circulation.  On  the  other  hand,  digitalis  does  not  re- 
move the  stenosis;  and  there  is  always  the  possibility  that  while 
the  obstruction  to  the  exit  of  blood  at  the  mitral  orifice  remains 
unchanged,  any  increased  output  from  a  right  ventricle  already 
dilated  and  hypertrophied  may  result  merely  in  increased  pul- 
monary engorgement.  This  shows  in  congestion  at  the  bases  of 
the  lungs,  transudation  of  fluid  into  the  pleural  cavity,  edema 
of  the  lungs,  or  hemorrhage  from  the  lungs. 

So  in  mitral  stenosis,  when  the  auricle  and  ventricle  are 
beating  in  normal  rhythm,  the  systemic  circulation  gets  but  little 
help  from  digitalis,  and  the  danger  of  congestion  in  the  lungs  is 
increased.  But  when  there  is  auricular  fibrillation — and  auric- 
ular fibrillation  is  more  common  with  mitral  stenosis  than  with 
any  other  lesion  of  the  heart — the  beneficial  effects  of  digitalis 
far  overshadow  any  possible  disadvantageous  ones. 

In  aortic  stenosis  the  aortic  orifice  is  narrowed  by  thickening 
of  the  valves  or  their  adherence  together,  so  that  the  blood  is 
impeded  in  its  passage  into  the  aorta.  The  result  is  that  the 
systemic  circulation  and  coronary  circulation  tend  to  be  inade- 
quate. In  an  attempt  to  force  more  blood  through  the  narrowed 
orifice  by  an  increased  power  of  systole  the  left  ventricle  is  dilated 
and  hypertrophied.  The  value  of  digitalis  would  not  be  inter- 
fered with  by  such  a  lesion. 

So  much  for  the  heart  lesions.  This  very  brief  review  of 
these  more  common  ones  will  serve  to  indicate  that  great  judg- 
ment must  be  employed  in  the  use  of  digitalis  in  heart  disease. 

But  it  must  not  be  forgotten  that  the  indication  for  digitalis 
is  failure  or  threatened  failure  of  compensation,  and  not  at  all  the 


DIGITALIS 


195 


mere  presence  of  a  valvular  lesion.  When  there  is  poor  compen- 
sation, whether  there  is  a  valvular  lesion  or  not,  digitalis  may  be 
the  best  drug  that  we  can  employ. 

In  aneurysm  of  the  aorta,  aortitis,  or  arteriosclerosis,  there  is 
no  contraindication  to  digitalis,  so  with  these  lesions,  as  without 
them,  its  use  would  depend  on  the  needs  of  the  heart.  In  pneu- 


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Fig.  24. — Case  with  mitral  stenosis  and  auricular  fibrillation.  V.S.,  ventricular 
systole;  R.P.,  radial  pulse.  Digipuratum  reduced  the  pulse  to  normal  rate, 
abolished  the  "pulse  deficit"  in  the  radial  pulse  as  compared  with  the  number  of 
ventricular  beats,  and  increased  the  urinary  flow,  as  shown  above.  At  the  same 
time  there  was  a  very  rapid  and  marked  disappearance  of  dyspnea,  cyanosis,  and 
venous  engorgement.  The  auricle  continued  to  fibrillate  (author's  case). 

monia  and  other  acute  infectious  diseases  digitalis  may  be  most 
useful  in  preventing  or  checking  auricular  fibrillation. 

There  is  no  condition  of  the  kidneys,  per  se,  which  calls  for 
digitalis.  Any  striking  diuretic  effect  is  obtained  only  in  condi- 
tions of  venous  engorgement  from  cardiac  failure. 

Summary  of  Therapeutics. — i.  The  indication  for  digitalis 


196          PHARMACOLOGY  AND  THERAPEUTICS 

is  failure  or  threatened  failure  of  compensation.  2.  Its  most 
striking  effects  are  seen  in  auricular  fibrillation  and  when  there  is 
venous  engorgement.  3.  The  drug's  efficiency  is  not  to  be  esti- 
mated by  its  effects  on  arterial  pressure.  4.  The  mere  presence 
of  a  valvular  lesion  is  not  a  reason  for  using  digitalis.  5.  The 
diuretic  effect  is  entirely  due  to  improved  circulation,  and  may 
be  evident  even  when  the  heart  weakness  has  not  yet  resulted  in 
obvious  edema  and  dropsy. 

The  Digitalis  Allies. — So  far  as  the  circulation  is  concerned, 
the  uses  of  these  are  the  same  as  those  of  digitalis  itself.  For 
administration  by  mouth  not  one  of  them  has  any  advantage 
over  digitalis  and  its  active  principles.  Convallaria  is  less  cer- 
tain, and  strophanthus  is  prone  to  cause  diarrhea,  while  both 
have  a  smaller  margin  of  safety  between  their  therapeutic  and 
poisonous  doses.  The  difference  between  digitalis  and  stro- 
phanthus in  their  action  upon  the  arteries  is  not  observed  in 
therapeutics.  Cushny  states  that  the  tincture  of  strophanthus 
when  mixed  with  water  deteriorates  and  becomes  inert  in  a  few 
days. 

But  for  intravenous  administration  strophanthin  and  ouabai'n 
are  the  most  suitable,  and  have  been  used  with  remarkable,  and 
in  some  instances  dramatic,  effects.  So  much  as  -fa  grain  (i  mg.) 
should  never  be  employed  intravenously  at  one  dose  if  the 
patient  has  just  previously  been  taking  any  of  the  drugs  of  the 
class  by  mouth.  But  it  may  be  employed  thirty-six  hours  after 
the  last  dose  of  strophanthus  by  mouth,  or  one  week  after  the 
last  dose  of  digitalis.  If  there  is  any  doubt,  the  beginning  dose 
should  not  exceed  ?$-$  grain  (|  mg.).  If  without  the  desired 
effect  it  may  be  repeated  in  two  hours. 

EPINEPHRINE 

Epinephrine,  more  familiarly  known  by  the  proprietary 
name  adrenaline,  is  an  animal  alkaloid  or  leukomain  obtained 
from  the  medullary  portion  of  the  suprarenal  glands,  chiefly  of 
cattle,  sheep,  and  pigs.  So  far  as  we  know,  it  is  the  same  as  the 
normal  internal  secretion  of  the  gland  in  man.  Its  formula  is 
NH.C6H3(OH)2.CHOH.CH2CH3)  and  it  is  a  distant  relative  of 
the  vasoconstricting  principle  of  ergot,  tyramine.  It  has  the 
properties  of  an  alkaloid,  hence  forms  salts,  is  precipitated  by 
alkalies,  tannic  acid,  etc.,  and  is  destroyed  by  long  contact  with 
alkalies.  In  the  dried  glands  it  is  present  to  the  extent  of  about 
i  per  cent. 

It  is  marketed  under  several  trade  names,  adrenaline,  supra- 
capsulin,  suprarenalin,  etc.,  in  a  solution  purporting  to  have  a 


EPINEPHRINE  197 

strength  of  i  part  of  the  chloride  in  1000.  This  solution  is  not 
decomposed  by  a  moment's  boiling,  so  it  may  be  sterilized  by 
heat.  By  prolonged  boiling  it  is  quite  changed.  On  long 
standing,  or  if  diluted,  it  deteriorates,  slowly  changing  to  a 
reddish  color  and  eventually  precipitating.  When  a  precip- 
itate is  present,  the  solution  should  be  discarded.  It  keeps 
better  when  it  contains  a  slight  excess  of  hydrochloric  acid. 
Tablets  of  the  hydrochloride,  the  pure  alkaloid,  and  the  tartrate 
are  also  obtainable.  A  synthetic  substitute,  suprarenin,  or 
dioxyphenyl-ethanol-methylamine  hydrochloride,  has  about  half 
the  strength  (Schultz). 

The  dried  suprarenal  glands  of  the  sheep  and  ox,  freed  from 
fat,  and  cleaned,  dried,  and  powdered,  are  official  under  the  title 
Suprarenalum  siccum.  This  dried  gland  is  about  six  times 
as  strong  as  the  fresh  gland,  and  is  used  either  in  tablet  form 
or  in  a  mixture  with  water.  The  latter  must  be  freshly  prepared, 
as  it  does  not  keep. 

Preparations  and  Doses. — The  dose  varies  according  to  the 
method  of  administration  and  the  effect  desired. 

Dried  Suprarenal  Gland. — Dose,  4  grains  (0.25  gm.)  by 
mouth. 

Solution  of  epinephrine  hydrochloride,  i  :  1000,  used  hypoder- 
matically  in  asthma,  urticaria,  etc.,  15  minims  (i  c.c.);  used  intra- 
venously, 2  minims  (0.12  c.c.);  or  in  shock,  30  minims  (2  c.c.) 
added  to  saline  and  very  slowly  administered.  Janeway  has 
administered  over  i  dram  (4  c.c.)  intravenously  in  a  little  more 
than  an  hour. 

On  testing  the  blood-pressure-raising  power  of  the  several 
commercial  preparations  as  compared  with  pure  solutions  of 
epinephrine,  Schultz,  Hunt,  and  others  found  them  to  be  of 
variable  efficiency  and  poor  keeping  quality. 

Pharmacology. — General  Action. — Epinephrine  is  a  stimu- 
lant of  sympathetic  nerve-endings  or  their  myoneural  junctions. 
As  Langley  puts  it,  "the  effects  of  epinephrine  upon  any  tissue 
are  such  as  follow  excitation  of  the  sympathetic  nerve  which 
supplies  the  tissue."  The  effects,  so  far  as  muscular  activity  is 
concerned,  depend  upon  the  degree  of  contraction  already  exist- 
ing. Thus,  with  greatly  relaxed  arteries,  the  proportional 
response  is  greater  than  with  arteries  in  normal  contraction ;  and 
with  contracted  bronchi  the  relaxation  is  greater  than  in  normal 
bronchi.  Hence  a  dose  which  will  constrict  relaxed  arteries  may 
not  affect  the  bronchi;  and  a  dose  which  will  relax  contracted 
bronchi  may  not  constrict  normal  arteries. 

Skin  and  Mucous  Membranes. — It  has  no  effect  on  the  un- 
broken skin,  but  when  applied  to  cuts,  open  wounds,  ulcers,  or 


198  PHARMACOLOGY    AND    THERAPEUTICS 

any  mucous  membranes  which  can  be  reached  (namely,  those  of 
the  conjunctiva,  lacrimal  duct,  nose,  throat,  mouth,  esophagus, 
stomach,  rectum,  vagina,  urethra,  and  bladder),  it  penetrates 
sufficiently  to  stimulate  the  vasoconstrictor  nerve-endings  of  the 
arterioles  at  the  site  of  application.  The  result  is  a  local  con- 
traction of  the  arterioles ;  and  this  is  so  marked  that  the  blood  is 
almost  shut  off  from  the  part,  the  tissues  shrink  and  appear 
blanched  from  comparative  bloodlessness,  and  any  moderate 
hemorrhage  is  checked.  This  local  contraction  of  the  arterioles 
is  greater  and  more  prompt  than  from  any  other  drug  in  use.  It 
follows  almost  instantly  the  application  of  the  epinephrine  and 
lasts  from  fifteen  minutes  to  one  or  two  hours.  Repeated  appli- 
cations will  continue  to  keep  the  arterioles  contracted  for  an 
indefinite  length  of  time. 

But  besides  vasoconstriction,  epinephrine  has  also  a  vaso- 
dilator action,  so  that  when  the  application  of  the  drug  is  stopped 
and  the  vasoconstriction  wears  off,  the  arterioles  not  only  relax 
again,  as  usual  after  constriction,  but  may  dilate  away  beyond 
the  normal — in  fact,  may  completely  lose  their  tone,  so  that 
there  may  be  a  late  return  in  marked  degree  of  the  condition 
which  the  epinephrine  was  intended  to  relieve,  viz.,  the  hemor- 
rhage, or  the  congestion,  or  the  relaxed  mucous  membrane. 
Cannon  and  Lyman  (1913)  bring  forward  some  evidence  against 
this  dilator  effect  being  due  to  stimulation  of  the  vasodilator 
nerves.  In  the  coronary  arteries,  the  dilator  effect  alone  is 
observed,  and  this  is  the  effect  on  other  arteries  after  the  adren- 
aline solution  is  boiled  for  a  length  of  time  (Lieb). 

Absorption  depends  upon  the  method  of  administration— 
i.  Applied  to  mucous  membranes,  or  given  by  mouth,  the 
drug  regularly  has  no  systemic  effect,  or  almost  none.  Possibly 
by  constricting  the  arteries  it  prevents  its  own  absorption.  It  is 
reported  that  an  aqueous  extract  of  two  pounds  of  fresh  supra- 
renal capsules  has  been  swallowed  without  apparent  ill  effect. 
Osborne  and  some  others  claim  that  it  is  slowly  absorbed  from 
the  mouth,  though  not  from  the  stomach,  while  some  have  found 
that  such  large  doses  as  ^  ounce  (15  c.c.)  of  the  i  :  1000  epi- 
nephrine solution  in  the  stomach  have  resulted  in  the  character- 
istic effects  on  the  circulation.  A  few  cases  also  are  reported 
of  marked  systemic  effects  from  its  application  to  the  conjunc- 
tiva, the  nose,  and  the  urethra.  But,  as  a  rule,  no  systemic  effect 
at  all  is  obtained  from  the  drug  when  it  is  given  by  mouth  or  applied 
to  mucous  membranes,  and  it  seems  to  be  rapidly  destroyed  at 
the  point  of  entrance  into  tissues  before  it  gets  into  the  circulation. 
Pilcher  has  shown  that  the  submucous  injection  in  the  nose  is 
very  rapidly  absorbed  and  may  produce  dangerous  effects. 


EPINEPHRINE  1 99 

2.  From  subcutaneous  injection  there  may  be  a  slight  rise  in 
arterial  pressure,   but  almost  always  there  is  no  measurable 
effect.     This  is  the  author's  experience  in  tests  with  students 
and  asthmatics.     There  is,  however,  a  fairly  prompt  effect  upon 
contracted  bronchi,  even  though  the  arteries  are  unaffected. 

3.  From  deep  intramuscular  injection  enough  seems  to  get 
into   the   blood-stream   to  induce   quite   frequently  a  distinct 
though  comparatively  small  rise  in  arterial  pressure  and  a  re- 
laxation of  the  bronchi.     These  effects  are  most  noticeable  when 
the  arteries  are  relaxed  or  the  bronchi  strongly  contracted. 

4.  From  intravenous  administration  there  is  an  immediate 
and  very  marked  rise  in  arterial  pressure.     This  is  the  only 
method  of  administration  for  a  sure  effect  upon  the  arteries. 

Circulation. — The  effect  of  an  intravenous  dose  upon  the 
circulation  is  a  marked  rise  in  arterial  pressure  and  a  momentary 
increase  in  rate,  followed  by  strengthened  and  slowed  heart. 
The  rise  in  pressure  is  only  momentary,  but  may  be  maintained 
by  repeating  the  dose  or  by  continuous  slow  infusion.  A  gradu- 
ated rise  in  pressure  may  be  obtained  by  intravenous  injection  of 
increasingly  large  doses. 

The  Vasoconstriction. — The  most  marked  constriction  is  in 
the  arteries  of  the  splanchnic  area,  where  it  may  be  so  great  that 
the  intestines  are  almost  bloodless.  It  is  produced  if  the  splanch- 
nic nerves  are  cut,  or  if  the  central  nervous  system  is  destroyed; 
therefore  it  is  due  to  a  peripheral  action  and  not  to  a  central  one. 
The  peripheral  effect  is  well  shown  in  an  isolated  viscus  or  an 
isolated  limb,  by  measuring  the  venous  outflow  before  and  after 
epinephrine.  In  perfusing  a  dog's  leg,  for  example,  the  outflow 
may  be  almost  entirely  stopped  by  the  addition  of  a  few  minims 
of  epinephrine  solution  to  the  perfusion  fluid,  but  no  such  action 
occurs  if  apocodeine  or  ergotoxine  has  previously  been  used  to 
paralyze  the  ends  of  the  vasoconstrictor  nerves.  Therefore 
the  site  of  the  stimulation  by  epinephrine  is  the  vasoconstrictor 
nerve-endings  or  the  myoneural  junctions  (Elliott).  After 
ergotoxine,  which  paralyzes  the  vasoconstrictor  endings  but  not 
the  vasodilators,  epinephrine  is  regularly  followed  by  vasodila- 
tion,  an  effect  known  as  the  "vasomotor  reversal"  of  Dale.  Hart- 
mann,  and  also  Haskins,  have  shown  that  after  intravenous  ad- 
ministration there  is  vasodilation  in  the  skeletal  muscles,  i.  e., 
the  blood  is  shifted  from  the  splanchnic  area  to  the  active  mus- 
cles, a  valuable  effect  in  shock.  The  coronary  arteries,  having  no 
vasoconstrictor  nerves,  are  dilated,  or  at  least  their  tone  dimin- 
ished so  that  they  become  dilated  (Janeway  and  Park).  Macht 
obtained  powerful  constriction  of  the  pulmonary  artery.  There 
is  some  evidence  that  the  cerebral  arteries  tend  to  be  dilated. 


200  PHARMACOLOGY    AND    THERAPEUTICS 

Janeway  and  Park  (1912)  have  shown  that  "the  effect  of 
epinephrine  on  an  excised  artery  in  a  physiologically  inert  solu- 
tion is  in  inverse  ratio  to  the  degree  of  tonus  possessed  by  that 
artery."  In  other  words,  it  is  to  be  expected  that  general  arterial 
relaxation  with  low  arterial  pressure,  as  in  Addison's  disease, 
will  give  a  greater  proportionate  response  to  the  drug  than  would 
a  normal  state  of  the  arteries  and  normal  arterial  pressure.  In 
a  case  of  Addison's  disease  at  St.  Luke's  Hospital,  15  minims 
slowly  administered  intravenously  caused  the  pressure  to  rise 
from  90  to  1 60  mm.  Haskins  and  Moore  have  established  the 
fact  that  normally  when  there  is  enough  epinephrine  in  the  blood 
to  give  a  pressor  effect,  the  intestines  become  paralyzed. 

Cameron  (1906)  determined  that  T^  grain  (0.6  gm.)  of  nitro- 
glycerin  was  just  enough  to  neutralize  the  pressure-raising  power 
of  0.0075  mg.  of  epinephrine  hydrochloride,  i.  e.,  about  8  minims 
(0.5  c.c.)  of  the  i  :  1000  solution. 

The  Slowing. — If  the  vagus  nerves  are  cut,  there  is  no  slowing 
of  the  heart,  or  at  least  if  there  is  slight  slowing,  it  is  abolished  by 
atropine;  therefore  the  slowing  must  be  due  to  stimulation  of  the 
vagus,  and  essentially  of  the  vagus  center.  But  if  the  arterial 
pressure  is  kept  low  by  bleeding  or  by  paralysis  of  the  vasocon- 
strictor endings  by  apocodeine  or  ergotoxine,  there  is  no  slowing. 
It  has  been  shown  also  that  the  slowing  always  follows  the  rise  in 
arterial  pressure.  Thus  it  is  evidently  due  to  the  reflex  stimula- 
tion of  the  vagus  which  regularly  occurs  when  the  arterial  pres- 
sure rises,  and  not  to  direct  stimulation  of  the  vagus  center  by 
the  drug.  Therefore  the  slowing  is  reflex,  and  is  dependent  upon 
the  rise  in  arterial  pressure,  and  not  upon  direct  vagus  stim- 
ulation. 

The  Increased  Force  of  the  Heart. — When  epinephrine  is 
slowly  added  to  the  perfusion  fluid  for  an  isolated  heart,  a 
myocardiograph  tracing  shows  increased  systolic  contraction  and 
lessened  diastolic  relaxation.  In  other  words,  there  are  increased 
contractility  and  increased  tonicity.  Atropine  to  paralyze  the 
vagus  endings  does  not  change  the  effect,  but  apocodeine  and 
ergotoxine,  which  paralyze  the  accelerator  endings,  abolish  it. 
Therefore  the  accelerator  endings  must  be  the  site  of  stimulation 
by  the  drug.  Some  investigators  believe  that  there  is  a  slight 
muscular  stimulation  in  addition. 

Thus,  in  an  intact  mammal,  epinephrine  slows  the  heart, 
increases  its  tone,  strengthens  its  beat,  and  dilates  its  coronary 
arteries.  It  also  constricts  the  systemic  arterioles.  The  manner 
in  which  these  effects  are  brought  about,  and  the  rapidity  of 
action,  are  entirely  different  from  those  of  digitalis.  The  rise 
in  arterial  pressure  is  very  great  and  very  prompt,  epinephrine 


EPINEPHRINE  2OI 

being  the  most  powerful  blood-pressure-raising  drug  that  we 
employ  in  medicine.  As  the  effect  is  peripheral  and  not  central, 
the  rise  occurs  even  when  the  vasoconstrictor  center  is  paralyzed 
or  exhausted,  but  it  lasts  only  from  one  to  five  minutes.  It  may 
be  kept  up  for  a  long  time  without  apparent  harm  by  frequently 
repeated  doses,  or  by  the  very  slow  administration  intravenously 
of  a  dilution  in  normal  saline  solution. 

From  quickly  repeated  large  doses  the  very  great  constric- 
tion of  the  arteries  may  result  in  failure  of  the  left  ventricle  with 
dilatation  and  weakness,  at  a  time  when  the  right  heart  is 
pumping  more  blood  into  the  pulmonary  arteries.  The  result  is 
pulmonary  edema.  This  effect  has  frequently  occurred  in  rab- 
bits from  i  or  2  c.c.  of  the  solution.  It  is  especially  likely  to 
occur  when  the  heart  is  already  impaired,  or  if  the  epinephrine 
is  given  rapidly  with  a  large  saline  infusion,  for  the  saline  liquid 
adds  to  the  diffusible  fluid  in  the  lung  capillaries. 

Blood. — Wiggers  was  unable  to  corroborate  the  finding  of 
Richards  and  Vosburgh  that  epinephrine  increases  the  coagula- 
bility of. the  blood,  but  Cannon  and  Gray  show  that  small  doses, 
o.ooi  mg.  per  kilo  intravenously,  and  larger  amounts  subcu- 
taneously,  shorten  the  coagulation  time  to  one-half  or  even  one- 
third,  though  when  added  to  drawn  blood  it  has  no  effect. 
Grabfield  finds  that  it  increases  the  prothrombin. 

Connective-tissue  Changes  in  the  Heart  and  Arteries. — In  1903 
Josue  described  sclerotic  lesions  of  the  aorta  in  rabbits  to  which 
epinephrine  had  been  administered  intravenously  for  long  periods. 
In  1906  Pearce  and  Stan  ton  injected  3  minims  of  the  i  :  1000 
solution  every  day  for  two  months,  and  obtained  not  only  these 
aortic  changes,  which  they  observed  to  be  due  to  degeneration 
and  calcification  in  the  muscular  tissue  of  the  media,  but  noted 
also  bulging  of  these  weakened  areas,  the  mechanical  breaking  of 
the  elastic  fibers,  and  the  actual  formation  of  aneurysmal  dilata- 
tions. Pearce  noted,  also,  some  connective-tissue  changes  in 
the  myocardium,  but  none  in  the  peripheral  arteries,  while  Erb 
found  arteriosclerotic  changes  in  the  other  arteries  as  well  as  the 
aorta.  Erb  attributes  the  effects  to  a  toxic  action  rather  than  to 
the  heightened  blood-pressure,  for  he  obtained  them  by  intra- 
peritoneal  injections  which  did  not  raise  blood-pressure.  The 
lesions  in  epinephrine-produced  arterioscleroses  differ  patholog- 
ically from  the  lesions  of  arteriosclerosis  in  human  beings,  but 
furnish  valuable  material  for  study.  Pearce  and  Hill  have 
later  questioned  the  role  of  epinephrine  in  the  production  of  some 
of  these  results,  as  they  found  arteriosclerotic  changes  quite 
common  in  supposedly  normal  rabbits. 

The  fear  of  producing  any  such  changes  by  the  therapeutic 


202  PHARMACOLOGY    AND    THERAPEUTICS 

use  of  the  drug  need  not  be  great,  for  we  never  administer 
epinephrine  repeatedly  for  long  periods  except  in  two  conditions, 
viz.,  disease  of  the  suprarenal  glands  and  bronchial  asthma.  The 
former  is  so  regularly  fatal  that  any  risk  may  be  taken  for  the 
chance  of  helping;  moreover,  the  theory  upon  which  epinephrine 
is  given  is  that  it  may  make  up  for  a  pathologic  deficiency  of  the 
natural  epinephrine  of  the  patient,  and,  therefore,  cannot  be 
present  in  the  system  in  excess.  This  theory  is  believed  to  be 
incorrect.  (See  Therapeutics.)  In  intractable  bronchial  asthma 
the  drug  may  be  used  repeatedly  by  hypodermatic  injection 
during  long  periods,  and  it  is  well  in  these  cases  to  think  of  the 
possibility  of  harm  to  the  arteries  and  heart,  and  to  the  nervous 
system. 

Respiratory  System. — Used  hypodermatically  in  small  quan- 
tities, epinephrine  causes  increased  depth  of  respiration;  while 
if  it  is  used  intravenously  it  quickens  respiration,  the  inspirations 
being  shallower.  Park  (1912)  found  that  when  it  was  applied 
to  excised  rings  of  the  bronchi  of  the  ox,  even  in  a  concentration 
as  low  as  i  :  10,000,000,  it  regularly  caused  relaxation  .without 
primary  constriction.  And  it  may  be  presumed  that  this  effect 
is  due  to  stimulation  of  the  bronchodilator  (sympathetic)  nerve- 
endings.  In  man,  when  it  is  given  hypodermatically,  it  produces 
a  decided  relaxation  of  contracted  bronchi.  The  rule  that  the 
drug  acts  best  where  the  condition  it  is  opposing  is  extreme, 
makes  it  peculiarly  valuable  in  spasmodic  asthma  due  to  exces- 
sive bronchial  contraction,  for  the  effect  on  the  bronchi  is  out  of 
proportion  to  the  effect  elsewhere,  and  is  often  evident  even 
when  the  arterial  pressure  is  not  affected  in  measurable  degree. 

Nervous  System. — Following  a  hypodermatic  dose,  as  for 
asthma,  there  is  frequently  an  immediate  onset  of  nervous  excite- 
ment and  agitation  which  may  last  as  much  as  an  hour  or  two. 

Alimentary  Tract. — The  local  astringent  effects  may  be 
obtained  in  mouth,  esophagus,  stomach,  and  rectum.  On 
intravenous  injection  the  drug  stimulates  the  ends  of  the  splanch- 
nic or  inhibitory  nerves  (which  belong  to  the  sympathetic 
system),  and  so  lessens  peristalsis  of  stomach  and  bowels.  The 
contractions  of  the  gall-bladder  are  said  to  be  inhibited  in  the 
same  way.  The  mucous  secretions,  the  saliva,  and  the  bile  are 
increased,  as  mentioned  below.  Pemberton  and  Sweet  (1912) 
have  shown  that  intravenous  injections  of  epinephrine  inhibit 
the  flow  of  pancreatic  juice;  and  Herter  found  that  painting  the 
pancreas  with  epinephrine  resulted  in  glycosuria. 

The  Eye. — A  drop  of  epinephrine  solution  in  the  eye  causes 
the  conjunctiva  to  become  shrunken  and  pale,  the  eyelids  to 
become  retracted,  and  the  eyeball  to  appear  more  prominent. 


EPINEPHRINE  203 

The  drug,  if  in  strong  solution,  also  penetrates  to  the  internal  eye, 
and  by  stimulation  of  the  sympathetic  nerve-endings  in  the 
fibers  of  its  radial  muscles  dilates  the  pupil.  A  solution  of 
i  :  1000  ordinarily  does  not  dilate  the  pupil;  but  Loewi  and 
Rosenberg  demonstrated  that  it  does  so  in  pancreatic  disease,  and 
in  any  condition  with  hyperglycemia,  such  as  hyper thyroidism, 
diabetes,  and  after  glucose  intravenously  or  freely  taken  by 
mouth.  Pratt  failed  to  obtain  the  reaction  in  three  dogs  with 
extreme  atrophy  of  the  pancreas.  As  a  test  for  epinephrine  in  a 
liquid,  Meltzer  and  Auer  make  use  of  the  extirpated  frog's  eye, 
which  regularly  reacts  to  a  strength  of  i  :  1000,  or  even  of  i  : 
10,000. 

Muscle.- — The  contraction  of  striped  muscle  is  not  affected, 
but  its  relaxation  is  greatly  slowed,  as  with  veratrine.  Smooth 
muscle  shows  the  effects  of  stimulation  of  sympathetic  nerve- 
endings.  Hoskins  claims  a  vasodilator  effect  in  the  skeletal 
muscles  with  increased  efficiency. 

Secretion. — The  sweat,  tears,  saliva,  bile,  and  mucus  are  in- 
creased by  stimulation  of  the  sympathetic  nerve-endings  in  the 
glands. 

Glands. — There  is  a  distinct  relation  between  the  thyroid 
and  adrenal  glands.  Increased  thyroid  secretion  as  in  exoph- 
thalmic goitre,  or  the  administration  of  thyroid  appears  to  sen- 
sitize the  sympathetic  nervous  system  to  epinephrine.  Hoskins 
states  that  feeding  adrenal  to  young  male  animals  leads  to 
hypertrophy  of  the  testes. 

Uterus. — Epinephrine  causes  constriction  of  the  uterine 
arteries  and  of  the  uterus  itself.  The  latter  effect  also  follows 
local  application  (as  in  an  intra-uterine  douche). 

Bladder. — Local  application  produces  an  astringent  effect 
upon  the  bladder  wall.  Intravenous  administration  results  in 
stimulation  of  the  ends  of  the  sympathetic  or  inhibitory  nerves 
of  the  bladder,  with  the  effect  of  relaxation  of  the  bladder  muscles. 
The  ureter  shows  increase  in  tone  and  rate  of  contraction. 

Urine. — Houghton  states  that  the  secretion  of  urine  is  in- 
creased synchronously  with  the  rise  in  arterial  pressure,  and 
continues  above  normal  for  several  minutes  after  blood-pressure 
falls.  He  believes  that  the  kidney  arteries  are  passively  dilated. 
In  five  experiments  the  arterial  pressure  showed  a  rise  of  from 
56  to  88  mm.  Hg,  and  the  urine  an  increase  of  from  8  to  30  minims. 
But  the  arterial  pressure  averaged  six  minutes  for  its  return  to 
normal,  while  the  urine  secretion  did  not  get  back  to  normal 
until  fifteen  minutes.  Some  observers  note  a  decrease  or  even 
cessation  of  the  urine  production  during  the  epinephrine  vaso- 
constriction.  It  is  an  interesting  observation  that  the  urine 


204  PHARMACOLOGY    AND    THERAPEUTICS 

may  be  found  to  contain  sugar,  and  this  has  been  proved  to  be 
due  to  an  excessive  amount  of  sugar  in  the  blood  from  lack  of 
dextrose  destruction.  It  is  an  artificial  diabetes,  which  occurs 
even  if  the  rise  in  blood-pressure  is  prevented.  It  does  not  occur 
if  the  animal  is  first  starved  until  its  stored  glycogen  is  all  used 
up.  Herter  and  his  associates  have  found  that  the  same  effect 
follows  when  the  pancreas  is  painted  with  epinephrine.  Kleimer 
and  Meltzer  find  the  increased  urination  and  glycosuria  more 
readily  produced  by  subcutaneous  than  by  intramuscular  in- 
jections. It  would  seem  that  the  diuretic  and  sugar-producing 
actions  are  quite  independent.  (See  "pupil  reaction"  above.) 

Metabolism. — Lusk  and  Richet  say,  "the  theory  that  epineph- 
rine causes  a  production  of  sugar  from  fat,  decreases  the  power 
of  the  organism  to  oxidize  glucose  through  inhibition  of  pancreatic 
function,  and  stimulates  the  thyroid  so  that  protein  metabolism 
is  increased  is  untenable  in  every  particular." 

Elimination. — The  fate  of  epinephrine  is  not  certainly  known. 
Falta  says  that  when  it  is  injected  subcutaneously  or  into  the 
peritoneal  cavity,  none  appears  in  the  urine,  while  when  given  by 
mouth,  though  it  has  no  systemic  effects,  it  is  eliminated  in  the 
urine. 

Toxicology. — From  the  local  use  of  the  drug,  there  have  been 
reports  of  overacting  heart,  palpitation,  and  vomiting.  These 
must  be  due  to  idiosyncrasy,  for  they  are  unusual.  After  the 
hypodermatic  or  intravenous  doses  there  is  frequently  excitement, 
with  tremor,  and  in  some  cases  much  anxiety.  Cushny  says 
that  the  hypodermatic  injection  of  very  large  doses  in  mammals 
results  in  excitement,  tremors,  and  paralysis  of  the  hind  limbs, 
and,  in  addition,  sometimes  vomiting,  increased  urination,  or 
hemorrhages  from  various  mucous  membranes  or  from  the  kid- 
neys. Death  occurs  either  from  paralysis  of  the  respiratory 
center  or  from  heart  failure,  due  to  back  pressure  from  the 
constricted  systemic  arteries.  There  is  no  doubt  that  some 
post-operative  cases  of  pulmonary  edema  are  due  to  the  use  of 
this  drug  with  saline  infusion. 

Epinephrine  and  Chloroform. — Levy  and  Lewis  (1912)  report 
a  research  on  cats,  regarding  the  simultaneous  use  of  these  two 
drugs.  They  found  that — (i)  Small  intravenous  injections  of 
epinephrine  chloride,  given  to  an  animal  under  high  percentages 
of  chloroform  vapor,  produce  a  condition  of  irritability  of  the 
ventricle,  with  irregular  and  rapid  heart;  and  that  (2)  low  ten- 
sion's of  chloroform  vapor  with  small  intravenous  injections  of 
epinephrine  chloride  ultimately  produce  the  highest  grade  of 
ventricular  disorder,  viz.,  ventricular  fibrillation,  which  means 
death.  Levy's  later  studies  corroborate  these  findings. 


EPINEPHRINE  205 

Therapeutics. — A.  For  local  effect  it  is  employed — i.  To 
cause  shrinkage  of  mucous  membrane,  whether  the  membrane  is 
normal,  or  swollen  and  hyperemic.  In  the  nose  such  shrinkage 
gives  a  clearer  view  for  examinations,  and  more  room  for  the 
passage  of  instruments,  such  as  a  Eustachian  catheter.  In  hay- 
fever  or  acute  catarrh,  i.  e.,  a  fresh  cold  in  the  head,  the  applica- 
tion of  an  epinephrine  solution  on  a  cotton  probe  almost  instantly 
shrinks  the  tissues  and  frees  the  stuffed-up  air-passages.  This 
effect  may  last  half  an  hour  or  more,  and  if  the  patient  then 
remains  quiet  and  in  a  warm  room,  may  persist  for  hours  after 
the  adrenaline  action  is  over.  In  hay-fever  the  adrenaline  solu- 
tion diluted  with  normal  saline  is  often  used  as  a  spray;  but  it 
might  be  noted  that  there  are  some  reports  of  chronic  turgescence 
or  hyperemia  following  its  frequent  use  in  this  condition.  In 
some  operations,  as  for  adenoids  and  hypertrophies,  the  shrink- 
age of  tissue  may  be  undesirable.  Dropped  in  the  eye,  it  may 
lessen  a  conjunctival  swelling,  and  so  favor  the  finding  and 
removal  of  a  foreign  body.  In  prolapse  of  the  rectum,  or  hemor- 
rhoids, the  shrinkage  may  enable  the  protruding  mass  to  be 
replaced. 

2.  To  arrest  a  small  hemorrhage — at  any  place  where  the  bleed- 
ing point  is  accessible,  as  in  the  nose,  stomach,  bladder,  etc.     In 
nose-bleed  the  hemorrhage  may  often  be  checked  by  a  pledget  of 
cotton  soaked  in  epinephrine  solution  and  applied  to  the  bleeding 
spot.     In  postpartum  hemorrhage  the  liquid  may  be  added  to  a 
hot  intra-uterine  injection  to  favor  uterine  contraction  and  per- 
haps to  constrict  the  uterine  arteries. 

3.  To  prolong  local  anesthesia  and  to  prevent  local  hemorrhage — 
it  is  added  to  solutions  of  cocaine  and  other  local  anesthetics. 
It  acts  by  vasoconstriction,  which  checks  the  rapid  removal  of 
the  anesthetic  by  the  blood-stream.     Berry  (1905)  showed  that 
the  toxic  action  of  cocaine  is  increased  when  it  is  administered 
with  epinephrine. 

4.  To  allay  itching  of  vulva  and  anus  it  may  be  applied  on 
cotton.     It  acts  on  the  moist  parts  of  the  vulva,  whether  mucous 
membrane  or  not. 

5.  In  anterior  poliomyelitis,  in  the  ascending  paralysis  types, 
spinal  injection  of  15  minims  (i  c.c.)  has  seemed  to  check  the 
progress  of  the  paralysis. 

B.  For  systemic  effect — it  is  administered  hypodermatically 
or  intravenously,  according  to  the  condition  to  be  treated. 

i.  Hypodermatically — (a)  to  overcome  bronchial  asthma,  a 
single  dose  of  15  minims  (i  c.c.),  (b)  to  check  anaphylactic  shock, 
and  (c)  in  Addison's  disease,  5  minims  (0.3  c.c.),  three  times  a  day. 
This  latter  is  a  condition  of  weakness  and  wasting,  with  pigmenta- 


206  PHARMACOLOGY   AND    THERAPEUTICS 

tion  of  the  skin  and  low  blood-pressure,  and  it  results  from  de- 
struction of  the  suprarenal  glands.  It  was  thought  that  doses 
of  epinephrine  might  take  the  place  of  the  natural  secretion  of 
these  glands,  but  reports  from  its  use  hypodermatically  or  by 
mouth  are  not  encouraging,  and  intravenous  administration 
several  times  a  day  in  chronic  disease  is  obviously  impossible. 
Loewi  found  2  cases  of  Addison's  disease  so  sensitive  to  epineph- 
rine that  dangerous  symptoms  followed  its  intravenous  use.  In 
our  own  experience  there  has  been  no  effect  on  the  course  of  the 
disease,  though  in  one  case  15  minims  (i  c.c.)  administered  slowly 
intravenously  caused  a  temporary  rise  in  systolic  pressure  from  90 
to  1 60  mm.  Others  report  temporary  improvement.  Osborne  rec- 
ommends the  whole  gland  in  the  form  of  tablets  which  are  allowed 
to  disintegrate  slowly  in  the  mouth.  As  a  matter  of  fact,  recent 
research  would  seem  to  indicate  that  the  manifestations  of  Addi- 
son's disease  are  not  due  merely  to  absence  of  epinephrine,  but 
also  to  the  loss  of  one  or  more  elements  from  the  cortex  of  the 
gland;  and  this  would  account  in  part  for  the  lack  of  benefit 
from  the  administration  of  epinephrine.  Epinephrine  will  not 
prolong  life  after  the  removal  of  the  adrenals. 

2.  Intravenously — it  is  employed  as  a  rapidly  acting  circula- 
tory stimulant  of  great  power  in  collapse  or  shock.  Owing  to  its 
ephemeral  action  and  to  the  impracticability  of  frequent  intra- 
venous doses,  it  is  suitable  only  in  emergencies,  and  is  not  em- 
ployed in  ordinary  conditions  of  failure  of  compensation.  It 
should  not  be  given  in  chloroform  collapse  (see  above).  For 
administration,  it  may  be  diluted  with  normal  saline  and  injected 
into  the  vein  by  a  syringe;  if  there  has  been  loss  of  blood,  it  may 
be  added  to  a  saline  infusion.  If  given  rapidly  with  a  saline 
infusion  when  there  has  been  no  loss  of  blood,  it  increases  the 
chances  of  pulmonary  edema  and  heart  failure,  but  a  good-sized 
dose  may  be  given  with  saline  if  the  infusion  is  carried  on  very 
slowly.  T.  C.  Janeway  states  that  he  has  seen  "the  most 
amazing  restoration  from  apparent  imminent  death  follow  the 
intravenous  injection  of  epinephrine  in  large  doses,  in  one  case 
over  i  dram  (4  c.c.)  of  the  i  :  1000  solution  in  a  little  more  than 
an  hour." 

Dangers. — A.  From  Local  Use. — i.  After  operations  (upon 
the  nose,  urethra,  etc.)  there  is  risk  of  late  hemorrhage  from 
secondary  vasodilatation. 

2.  In  hay-fever  there  is  risk  of  a  chronic  state  of  vascular 
dilatation  following  the  frequent  use  of  the  drug. 

B.  From  Intravenous  Administration. — i.  In  cerebral  arterio- 
sclerosis there  is  risk  of  rupture  of  a  cerebral  artery  from  any  sud- 
den great  rise  in  general  blood-pressure. 


PITUITARY    EXTRACT  2O7 

2.  In  internal  hemorrhage,  especially  cerebral  or  pulmonary, 
there  is  risk  of  increasing  the  hemorrhage. 

3.  In  pulmonary  edema  there  is  risk  of  increasing  the  edema. 

4.  In  emergencies  there  is  risk  of  precipitating  heart  failure 
and  producing  pulmonary  edema  or  general  edema. 

PITUITARY  EXTRACT 

Pituitary  extract  (hypophysis  sicca,  desiccated  hypophysis}  con- 
sists of  the  posterior  lobe  of  the  pituitary  gland  of  cattle,  cleaned, 
dried,  and  powdered.  Dose,  grain  |  (0.03  gm.).  A  solution, 
liquor  hypophysis,  containing  the  water-soluble  principles  from  the 
posterior  lobe  is  also  official.  Subcutaneous  dose,  15  minims  (i 
c.c.).  This  amount,  diluted  20,000  times,  is  required  by  the 
Pharmacopoeia  to  have  the  same  activity  on  the  isolated  uterus 
of  the  virgin  guinea-pig  as  a  i  :  20,000,000  solution  of  beta- 
iminazolylethylamine  hydrochloride  (see  Ergot).  Roth  found 
commercial  preparations  exceedingly  variable.  So  far  the  pos- 
terior lobe  has  yielded  no  active  principle.  Its  activity  is  not 
destroyed  by  boiling  (Gushing).  The  anterior  lobe  and  pars 
intermedia  are  not  official.  (See  below.) 

Pharmacologic  Action.- — The  main  action  of  the  drug  is  to 
stimulate  smooth  muscle.  It  is  in  some  degree  antagonistic  to 
the  anterior  lobe,  as  it  tends  to  diminish  sexual  development  and 
activity  (Goetsch). 

Locally. — Applied  to  mucous  membranes  or  injected  beneath 
the  skin  it  causes  moderate  constricton  of  the  arterioles. 

Circulation. — The  intravenous  administration  induces  slowing 
and  weakening  of  the  heart  and  a  rise  in  arterial  pressure,  the 
rise  beginnning  in  a  minute  or  less  and  lasting  usually  from  5  to 
10  minutes,  though  occasionally  for  as  much  as  half  an  hour. 
The  administration  of  atropine  or  cutting  the  vagi  results  in 
strengthening  both  auricle  and  ventricle,  with  an  added  rise  in 
pressure  (Lieb) .  The  rise  in  pressure  takes  place  in  a  decapitated 
cat  and  is  therefore  not  clue  to  an  effect  on  the  vasoconstrictor 
center.  The  maximum  rise  in  pressure  may  be  as  great  as  that 
from  epinephrine,  but  is  more  slowly  attained.  There  is  practi- 
cally no  circulatory  effect  from  a  subcutaneous  dose,  and  as  a 
rule  only  a  slight  one  from  an  intramuscular  injection.  From 
intramuscular  doses  Schmidt  obtained  regularly  a  rise  in  diastolic 
pressure,  though  no  constant  effect  on  the  systolic  pressure. 

Its  effects  therefore  resemble  those  from  epinephrine,  but  there 
is  a  marked  difference  in  the  site  of  action.  For  after  apocodeine 
or  ergotoxine,  while  the  effect  of  epinephrine  changes  to  vaso- 
dilatation,  pituitary  constricts  the  arteries  as  much  as  it  did 
before.  Furthermore,  pituitary  constricts  the  coronary,  pulmon- 


208 


PHARMACOLOGY   AND    THERAPEUTICS 


ary,  and  cerebral  arteries.    Hence  it  must  act  by  stimulating  the 
arterial  muscles  and  not  the  vasoconstrictor  myoneural  junctions. 


T3    ( 

•3 


j_>  <U 
<  G 
^S 

i"s 


G   6r  5 


With  isolated  arteries  the  doses  may  be  repeated  indefinitely, 
with  vasoconstriction  as  the  invariable  result.  In  the  intact 
animal  McCord  reported  a  fall  in  arterial  pressure  after  several 


PITUITARY   EXTRACT  2OQ 

repetitions  of  the  dose,  attributing  it  to  the  conversion  of  the 
constrictor  action  into  a  peripheral  dilator  effect  on  the  arterial 
muscles;  but  Lieb  and  Bastedo  failed  to  obtain  any  dilator  effect 
from  nine  successive  large  doses.  Hewlett  claims  that  it  is  the 
only  drug  that  will  convert  the  abnormal  pulse  form  seen  in 
fever  to  the  normal  pulse  form. 

Blood. — Kahn  and  Gordon  report  a  reduction  in  coagulation 
time  in  fifteen  minutes  after  a  hypodermic  injection. 

Intestines. — Both  subcutaneous  and  intravenous  doses  have 
usually  a  marked  effect  on  the  muscles  of  the  intestines,  causing 
increased  tone  and  peristalsis  even  in  so-called  paralytic  distention 
of  the  bowel.  But  Shamoff  (1916)  reported  depression  in  some 
cases  in  isolated  segments  of  the  small  intestine,  and  Hoskins 
reports  depression  of  tonus  and  peristalsis  in  the  intact  animal 
in  five  dogs  out  of  six  after  the  intravenous  injection  of  com- 
mercial pituitrin. 

Kidneys. — In  perfusing  the  isolated  kidney  in  an  oncometer 
the  addition  of  pituitary  regularly  results  in  a  diminution  in  size 
with  a  lessened  venous  output  owing  to  local  arterial  constriction. 
But  in  an  intact  animal,  the  intravenous  or  subcutaneous  dose 
results  in  increased  volume  (after  a  primary  shrinkage),  increased 
venous  output,  and  increased  urination  which  may  last  as  much 
as  thirty  minutes.  Pilcher  and  Sollmann  have  shown  that  there 
is  no  effect  on  the  vasomotor  centers,  and  Lieb  finds  that  the 
diuresis  depends  directly  on  the  rise  in  arterial  pressure.  On  the 
other  hand,  destruction  of  the  posterior  lobe  results  in  polyuria, 
and  in  this  and  other  forms  of  polyuria  the  administration  of 
pituitary  has  resulted  in  diminished  urination  (see  below). 
Motzfeldt  says  that  it  does  this  whether  given  by  mouth,  sub- 
cutaneously,  or  intravenously.  It  stimulates  both  the  ureteral 
and  bladder  muscles. 

Other  External  Secretions. — Following  Schaefer's  report  that 
it  increased  the  amount  of  milk,  Hill  and  Simpson  found  that,  ad- 
ministered to  a  nursing  animal  subcutaneously,  intramuscularly, 
or  intravenously,  it  caused  an  immediate  marked  increase  both 
in  the  amount  of  milk  and  in  its  fat  content,  but  that  this  was 
compensated  for  by  a  diminished  secretion  of  poor  milk  so  that 
the  total  change  in  twenty-four  hours  was  practically  none. 
In  three  experiments  on  a  woman  in  the  fifth  month  of  lactation 
15  minims  (i  c.c.)  of  pituitrin,  equivalent  to  |  grain  (20  mg.) 
of  dried  posterior  lobe,  resulted  in  a  few  minutes  in  a  marked 
increase  of  secretion  and  an  increase  in  the  fat  average  from  3.4 
to  5.5  per  cent.  It  has  been  suggested  that  the  action  is  one 
of  stimulation  of  the  smooth  muscle  in  the  gland  whereby  the 
already  formed  milk  is  expressed  more  rapidly. 
14 


210  PHARMACOLOGY   AND   THERAPEUTICS 

Subcutaneous  injections  tend  to  inhibit  the  flow  of  saliva 
and  pancreatic  juice.  Weed  and  Gushing  found  an  increase  in 
the  rate  of  production  of  cerebrospinal  fluid  through  stimulation 
of  the  secretory  activity  of  the  choroid  plexus. 

Internal  Secretions. — According  to  Pal,  subcutaneous  injec- 
tions have  no  effect  on  normal  thyroids,  but  in  hyperthyroidism 
reduce  the  excessive  thyroid  secretion  with  disappearance  of  the 
acute  symptoms.  He  reports  good  results  in  16  cases  of  exoph- 
thalmic goiter;  others  report  similar  results.  In  diabetes  in- 
sipidus,  which  is  believed  to  be  due  to  the  lack  of  pituitary  secre- 
tion, the  drug  is  able  to  check  the  polyuria.  Goetsch  found  that 
the  administration  either  subcutaneously  or  intravenously  lowers 
the  sugar  tolerance. 

Uterus. — An  isolated  guinea-pig  uterus  beating  regularly  and 
strongly  in  Ringer's  solution,  shows  an  immediate  response  to  the 
addition  of  pituitary.  The  tonus  is  markedly  increased,  the 
individual  contractions  are  shorter,  and  the  relaxations  are 
somewhat  quicker.  The  uterus  may  go  into  tetanic  con- 
traction. 

The  effect  on  the  human  uterus  removed  at  operation  has 
been  well  studied  by  Lieb,  by  the  strip  method.  On  the 
addition  of  pituitary  the  movements  of  the  parturient  uterus  be- 
came stronger  and  more  rapid,  and  the  tone  was  greatly  increased. 
Except  in  one  instance,  and  that  after  a  very  large  amount  of 
pituitary,  there  was  no  tetanus,  a  fact  also  noted  in  clinical 
use.  The  Fallopian  tubes  showed  an  increased  rate  of  contrac- 
tion without  any  increase  in  strength.  On  the  non-pregnant 
uterus  and  tube  there  was  either  no  effect  or  a  distinct  depression. 
It  is  of  interest  that  during  pregnancy  the  anterior  and  middle 
division  of  the  pituitary  gland  enlarge,  but  not  the  posterior, 
while  only  the  posterior  lobe  extracts  stimulate  the  uterus. 
It  therefore  seems  probable  that  in  pregnancy  some  substance, 
possibly  produced  in  the  anterior  lobe,  sensitizes  the  uterus  to  the 
product  of  the  posterior  lobe. 

Toxicology. — In  isolated  dog  hearts  the  author  has  seen  mani- 
festations of  overexcitation  of  the  heart  with  premature  beats 
and  marked  weakening  of  both  auricle  and  ventricle.  Such  condi- 
tions have  been  reported  after  its  use  in  human  obstetrics.  Other 
reported  untoward  effects  from  its  use  in  labor  are:  rupture  of  the 
uterus,  postpartum  uterine  atony,  contraction  of  the  previously 
dilated  os,  premature  separation  of  the  placenta,  lacerations  of 
the  cervix  and  perineum,  weakening  and  slowing  of  the  fetal 
heart-sounds,  and  asphyxia  of  the  fetus  from  the  powerful  and 
frequent  contractions  of  the  uterus.  DeLee,  1916,  cites  18  cases 
of  rupture  of  the  uterus.  Vogt,  basing  his  report  on  7600 


PITUITARY    EXTRACT  211 

labors,  emphasizes  the  frequency  of  untoward  symptoms  and 
cites  cases  of  maternal  collapse  from  cardiac  weakness,  and  cases 
of  death  of  the  fetus  from  pressure.  Mundell  summed  up  3952 
cases  in  1914  and  1293  cases  in  1916.  In  the  latter  group  there 
were  12  cases  of  ruptured  uterus,  34  cases  of  fetal  death,  and  40 
cases  of  asphyxia  pallida.  He  states  that  because  of  the  fre- 
quency of  bad  effects  on  both  child  and  mother  its  field  of  use- 
fulness in  obstetrics  is  a  limited  one.  The  consensus  of  opinion 
is  that  it  should  not  be  employed  except  in  cases  of  uterine 
inertia  and  then  only  when  the  cervix  is  effaced. 

Anterior  Lobe. — The  anterior  lobe  and  pars  intermedia  have 
entirely  different  effects  and  uses  from  those  of  the  posterior  lobe. 
They  have  a  powerful  influence  in  the  establishment  of  normal 
skeletal  and  sexual  development,  and  their  disease  or  atrophy 
results  in  sexual  retrogression  in  adults.  Goetsch  and  others 
have  found  that  the  administration  of  anterior  lobe  extracts  to 
young  animals  results  in  more  rapid  growth  and  development, 
coarser  and  drier  hair,  larger  nipples  in  the  female,  more  rapid 
development  of  the  sexual  glands  of  both  sexes,  with  earlier  sex 
maturity  and  increased  sexual  activity.  In  pituitary  infantilism 
or  dwarfism  the  anterior  lobe  has  proved  of  distinct  value. 
Gushing  and  his  associates  have  demonstrated  that  the  condition 
known  as  dystrophia  adiposo-genitalis,  with  lethargy,  slowed  vital 
functions,  loss  of  sexual  activity  and  a  tendency  to  great  ac- 
cumulation of  fat,  is  similar  to  that  at  the  onset  of  hibernation 
in  animals,  at  which  time  the  anterior  lobe  is  atrophied.  It  is 
relieved  by  anterior  lobe  extract.  In  premature  menopause  with 
hypertrichosis,  obesity,  etc.,  it  has  been  used  with  good  effect. 
In  asthma  Warfel  reported  good  results  in  13  cases  from  10  grains 
(0.7  gm.)  of  dried  anterior  lobe  daily,  and  Zueblin  from  the  sub- 
cutaneous use  in  combination  with  epinephrine.  Robertson 
claims  to  have  obtained  an  active  growth-controlling  principle 
from  the  anterior  lobe,  the  yield  of  the  ox  pituitary  averaging 
10  mg.  He  calls  it  tethelin. 

Whole  Gland. — Goetsch  suggests  that  the  whole  gland  con- 
tains opposing  elements,  the  posterior  lobe,  for  example,  antagon- 
izing the  effect  of  the  anterior  lobe  on  sexual  development. 
Musser  gave  an  extract  of  the  whole  gland  by  mouth  to  18  persons 
for  periods  of  one  week  to  ten  months,  using  tablets  equivalent  to 
0.26  gm.  of  fresh  gland.  There  was  no  effect  noted  from  less 
than  four  tablets  a  day.  The  blood-pressure  showed  a  rise  in 
17  out  of  1 8  patients,  the  heart  rate  usually  an  increase,  but  a 
decided  decrease  in  two,  diuresis  occurred  in  six  patients,  and 
diarrhea  in  seven,  while  daily  movements  of  the  bowel  appeared 
in  four  that  had  been  previously  constipated. 


212  PHARMACOLOGY   AND   THERAPEUTICS 

Therapeutics. — Hypophysis  liquid  is  employed  intravenously 
in  shock  and  intramuscularly  or  subcutaneously  in  uterine  inertia 
and  in  tympanites  or  intestinal  paralysis  as  in  pneumonia  or  fol- 
lowing operations.  A  dose  of  15  minims  (i  c.c.)  may  be  repeated 
in  one  hour  if  necessary,  and  every  two  to  four  hours  thereafter. 
Undoubtedly  the  drug  is  highly  valuable  in  these  conditions. 
Quigley,  Humpstone,  Hirsch,  and  others  claim  that  it  will  not 
induce  labor.  Others  point  out  that  it  does  not  bring  about  a 
tetanic  contraction  and  is  therefore  not  of  use  in  postpartum 
hemorrhage. 

BARIUM 

The  common  soluble  salts  of  barium  (barium)  are  the 
chloride  and  the  nitrate,  dose,  i  grain  (0.06  gm.).  They  are 
little  employed  except  in  pharmacologic  laboratories  and  in 
veterinary  practice.  Barium  has  been  found  in  the  western 
"loco- weed"  (mad- weed),  which  is  popularly  believed  to  be 
the  cause  of  hallucinations  and  destruction  in  cows,  sheep, 
and  horses.  Alsberg  and  Black  believe  it  to  be  present  in  too 
small  quantity  to  be  responsible  for  the  "loco"  disease,  and 
Marshall  found  that  all  the  symptoms  attributed  to  loco-weed 
could  be  accounted  for  by  undernourishment  and  infections  such 
as  liver  tape- worm.  He  further  found  that  sheep  fed  with  loco- 
weed  and  alfalfa  kept  well-nourished  and  showed  no  "loco" 
symptoms.  Barium  is  therefore  not  the  cause  of  the  "loco" 
symptoms. 

Barium  is  locally  irritant  and  is  a  powerful  direct  stimulant 
of  all  forms  of  muscle.  Smooth  muscle  may  go  into  tonic  con- 
traction, while  striped  muscle  shows  increased  contraction  and  a 
prolonged  time  for  relaxation — the  so-called  veratrine  action. 
The  contraction  is  more  deliberate  than  that  produced  through 
nerve  stimulation.  Absorption  is  so  slow  that  the  drug  acts  as  a 
cathartic,  the  chloride  being  used  for  this  purpose  in  veterinary 
practice.  From  excessive  muscular  contraction  there  may  be 
vomiting,  diarrhea,  or  colic.  Barium  sulphate  is  bland  and 
has  been  employed  to  outline  the  alimentary  tract  for  #-ray 
pictures. 

Circulatory  System. — As  the  result  of  direct  stimulation  of 
the  heart  muscle,  the  systolic  contraction  is  more  complete  and 
the  diastolic  relaxation  less  so,  and  this  tendency  may  progress 
until  but  little  blood  is  expelled  at  each  systole.  After  death  the 
frog's  heart  is  firmly  contracted  in  systole.  The  arterioles, 
including  the  pulmonary,  cerebral,  and  coronary,  which  have  no 
vasoconstrictor  nerves,  are  strongly  contracted  from  muscular 
stimulation;  and  characteristically  the  contraction  develops  more 


CAMPHOR  213 

slowly  and  is  of  longer  duration  than  arterial  contraction  brought 
about  by  impulses  through  the  vasoconstrictor  nervous  mechan- 
isms. 

The  uterus,  the  bladder,  and  other  organs  are  also  strongly 
contracted.  There  are  some  peculiar  effects  upon  the  central 
nervous  system,  resulting  in  hallucinations  and  other  "loco" 
phenomena,  and  death  is  preceded  by  tonic  and  clonic  convul- 
sions. The  chemic  antidote  in  the  alimentary  tract  is  any  sol- 
uble sulphate,  for  this  forms  the  insoluble  barium  sulphate.  It 
should  be  removed  from  the  stomach  by  lavage  or  an  emetic. 
The  systemic  treatment  of  poisoning  is  symptomatic,  the  nitrites 
being  the  best  drugs  to  counteract  the  general  vasoconstriction. 

CAMPHOR 

Camphor  (camphora,  <z)  is  a  stearopten,  C9Hi6CO,  which  is 
chemically  a  ketone.  It  is  made  synthetically  or  is  obtained  by 
boiling  the  twigs  and  wood  of  Cinnamomum  camphora  (Fam. 
Lauracece)  with  water,  and  condensing  the  distillate.  The  cam- 
phor tree  is  an  evergreen  of  Japan  and  China,  and  has  been  intro- 
duced into  the  southern  United  States  for  ornamental  purposes. 
Camphor  is  a  volatile,  inflammable,  gummy  substance,  freely 
soluble  in  alcohol,  ether,  chloroform,  and  the  fixed  and  volatile 
oils.  In  water  it  is  soluble  to  the  extent  of  about  8  parts  in  1000, 
just  enough  to  impart  to  the  water  a  strong  odor  and  taste. 
Though  of  a  gummy  nature,  it  may  be  powdered  on  the  addition 
of  a  little  alcohol  or  chloroform.  Its  mixtures  with  menthol, 
salol,  chloral  hydrate,  thymol,  and  some  other  solids  become 
liquid  without  apparently  undergoing  any  chemic  change. 

Preparations  and  Doses. — 
Camphor,  2  grains  (0.13  gm.). 
Water,  0.8  per  cent.,  2  drams  (8  c.c.). 
Spirit,  10  per  cent.,  20  minims  (1.3  c.c.). 
Liniment  (camphorated  oil),  20  per  cent. — for  external  use. 

Camphor  is  also  an  ingredient  of  soap  liniment,  chloroform 
liniment,  menthol-camphor,  N.  F.  (menthol,  i;  camphor,  i), 
chloral-camphor,  N.  F.  (chloral  hydrate,  i;  camphor,  i),  rhinitis 
tablets  (see  Belladonna),  and  various  diarrhea  remedies.  Among 
these  latter,  two  well-known  ones  are  "Sun  Cholera  Drops" 
and  "Squibb's  Diarrhea  Mixture.'"  (See  Anti-cliarrheics.)  An 
allied  product  is  monobromated  camphor  (camphora  mono- 
bromata),  i.  e.,  camphor  in  which  one  H  has  been  replaced  by 
bromine,  C9Hi5BrCO.  It  is  used  for  its  bromine  as  a  nerve 
sedative,  dose,  2  grains  (0.13  gm.). 

Pharmacologic  Action. — Micro-organisms  and  Insects. — Cam- 


214  PHARMACOLOGY  AND  THERAPEUTICS 

phor  is  moderately  antiseptic.  Its  odor  is  disliked  by  insects, 
and  it  is  used  to  drive  away  moths,  mosquitos,  etc. 

Skin. — If  a  strong  preparation  is  rubbed  into  the  skin  or 
kept  in  contact  with  it  for  some  time,  it  is  counterirritant,  exert- 
ing a  "rubefacient"  effect,  i.  e.,  it  irritates  the  skin  and  dilates 
the  skin  vessels  so  that  the  part  becomes  red  and  warm.  It 
should  be  covered  with  a  piece  of  flannel  or  oiled  silk  to  prevent 
evaporation.  If,  however,  camphor  dissolved  in  alcohol,  as  in 
spirit  of  camphor,  is  applied  and  allowed  to  evaporate,  it  has 
just  the  opposite  effect,  that  is,  blanches  and  cools  the  part. 

Mucous  Membranes. — Camphor  irritates  mucous  membranes 
and  causes  them  to  contract,  and  for  this  and  its  antiseptic 
property  is  considered  useful  in  nasal  therapeutics. 

Alimentary  Tract. — The  solid  gum-camphor  is  chewed  with 
pleasure  by  some  people,  but  to  most  has  a  biting  taste  and  is 
nauseating.  In  solution  it  has  a  strongly  carminative  action, 
and  in  strong  doses  may  be  so  irritant  as  to  cause  vomiting.  In 
the  intestines  it  is  believed  to  check  secretion,  though  this  point 
is  not  definitely  established.  It  is  said  also  to  be  antiseptic  in 
the  intestines,  because  in  a  series  of  tests  it  was  shown  to  decrease 
the  ethereal  sulphates  of  the  urine. 

Absorption. — It  is  absorbed  readily  from  stomach  and  intes- 
tines, and,  if  used  hypodermatically,  from  the  tissues.  When 
used  hypodermatically  it  is  irritant. 

Circulatory  Organs. — Before  Absorption. — When  the  drug  is 
swallowed  in  strong  enough  solution  to  have  marked  local  action 
on  the  mouth,  there  is  at  once  a  moderate  acceleration  of  the 
rate  of  the  heart  corresponding  with  that  obtained  from  other 
members  of  the  volatile  oil  series.  It  is  solely  a  reflex  effect. 

After  Absorption. — Any  good  effects  upon  the  circulation  are 
extremely  problematic,  the  ones  reported  being  mild  stimulation 
of  the  heart  muscle  and  mild  stimulation  of  the  vagus  and  vaso- 
constrictor centers.  In  normal  animals  the  rate  and  force  of 
the  heart  continue  about  the  same,  and  the  total  output  of  the 
heart  is  either  not  affected  at  all  or  is  slightly  increased.  There 
is  also  a  dilatation  of  the  skin  vessels,  but  this  does  not  essen- 
tially affect  general  arterial  pressure. 

The  stimulation  of  the  vasoconstrictor  center  is  an  uncertain 
quantity,  for  at  times  there  is  no  stimulation;  while  when  there 
is  stimulation,  it  may  be  intermittent,  so  that  periods  of  lowered 
arterial  pressure  alternate  with  periods  of  raised  arterial  pressure. 
There  may  be  slowing  of  the  heart  and  a  fall  in  blood-pressure. 
Hence,  as  a  vasoconstrictor,  camphor  ranks  low.  In  fact, 
Likhatcheva  reports  dilatation  of  the  peripheral  and  coronary 
arteries  from  perfusion  with  solutions  of  i  :  5000  to  i  :  2500. 


Aur. 


Fig.  29. — Camphor  in  oil,  20  mg.  per  kilo  intravenously.  Little  effect  on 
auricle  and  ventricle.  Fall  in  arterial  pressure  from  91  to  78.  Pulse  somewhat 
slowed.  (Tracing  made  by  Dr.  C.  C.  Lieb.) 


CAMPHOR  215 

Cushny  says  of  it,  "in  man  and  animals  the  heart  is  sometimes 
slowed,  but  is  generally  little  affected  in  either  strength  or  rate," 
and,  "the  slight  dilatation  of  the  vessels  (of  the  skin)  is  the  only 
change  in  the  circulation,  unless  quantities  sufficient  to  cause  con- 
vulsions are  injected."  Gottlieb  and  Meyer  (1910)  agree  with 
Cushny  so  far  as  normal  laboratory  animals  are  concerned. 
"Thus,"  they  say,  "camphor  cannot  ordinarily  be  considered  a 
circulatory  stimulant.  But  in  the  conditions  of  circulatory 
failure,  where  stimulus  production  in  the  heart  threatens  to  fail, 
camphor  is  undoubtedly  to  be  considered  a  heart  stimulant. 
For  in  perfusion  camphor  will  overcome  the  fibrillation  of  the 
auricle  which  is  caused  by  chloroform  and  other  poisons,  and 
even  that  from  electric  stimulation,  and  it  will  prevent  the  excess- 
ive slowing  and  weakening  brought  on  by  chloral  hydrate." 
Heinz  says  practically  the  same. 

In  one  case  of  septicemia  in  which  the  author  injected  5 
grains  (0.3  gm.)  of  camphor  in  oil  hypodermatically  three  times 
a  day  for  two  days  there  occurred,  on  three  occasions,  for  about 
two  hours  after  the  dose,  a  distinct  weakening  of  the  heart,  with 
depression  of  the  respiration  and  Cheyne-Stokes  breathing. 

Heard  and  Brooks  (1913)  tested  camphor  on  human  beings. 
In  5  cases  with  normal  circulation  a  hypodermatic  of  camphor, 
20  grains  (1.3  gm.)  in  oil,  showed  in  four  no  change  in  the  circula- 
tion, and  in  the  other  one  a  fall  of  17  mm.  in  systolic  and  25  mm. 
in  diastolic  pressure.  In  9  cases  with  auricular  fibrillation  and 
other  cardiovascular  conditions  there  was  no  change,  except  in 
2  of  them  a  very  slight  rise  in  pressure.  Their  observations  were 
made  for  from  forty  to  two  hundred  and  seventy  minutes  after 
the  injection.  The  only  rises  in  pressure  were  in  cases  with 
great  mental  excitement,  and  in  these,  on  a  second  test,  there  was 
no  rise.  Even  as  much  as  50  grains  (3.3  gm.)  failed  to  pro- 
duce any  definite  effects,  either  desirable  or  toxic.  In  perfusing 
a  cat's  isolated  heart,  camphor  in  saturated  solution  was  without 
effect  on  the  normal  heart,  but  in  2  instances  checked  experi- 
mental fibrillation.  Leo  (1913)  obtained  a  rise  of  20  to  30  mm. 
mercury  from  200  c.c.  of  a  saturated  solution  in  Ringer's 
fluid. 

We  do  not  think  it  should  be  used  as  a  heart  stimulant  at  all, 
except  as  a  single  dose  in  emergency.  Even  then  it  is  entirely 
unreliable.  (See  Fig.  57,  page  458.) 

Respiratory  Organs. — As  with  other  carminatives,  there  is 
a  reflex  stimulation  from  the  stomach  or  mouth.  Systemically, 
after  large  doses,  there  is  some  stimulation  of  the  respiratory 
center.  Edsall  and  Means  found  this  stimulation  very  slight. 
It  is  thought  that  some  of  the  drug  is  eliminated  in  the  bronchial 


2l6  PHARMACOLOGY   AND   THERAPEUTICS 

mucus;  but  if  this  is  so,  the  dose  of  a  few  grains  is  too  small  for 
any  effective  remote  local  action. 

Cerebrum. — Given  by  mouth,  camphor  tends  to  lessen  hys- 
teric excitement  and  nervous  instability.  All  strong  carmina- 
tives do  this  to  some  extent,  but  camphor,  valerian,  and  a  few 
other  drugs  seem  to  exert  an  antihysteric  influence  quite  out  of 
proportion  to  their  value  as  carminatives.  This  probably  is  the 
effect  of  stimulation  of  the  higher  controlling  centers  of  the  brain 
(those  governing  reason,  self-control,  will,  etc.).  That  cam- 
phor is  a  cerebral  stimulant  is  shown  by  increased  intellectuality, 
and  by  the  appearance,  after  excessive  doses,  of  delirium, 
maniacal  excitement,  motor  restlessness,  and  even  epileptiform 
convulsions. 

Medulla. — The  slight  stimulation  of  the  respiratory  and  vagus 
centers  and  the  intermittent  stimulation  of  the  vasoconstrictor 
center  have  been  mentioned  above. 

Peripheral  Nerves. — Prolonged  application  to  the  skin  of  a 
strong  preparation,  such  as  menthol-camphor,  results  in  a  lessen- 
ing of  the  pain  sense  from  depression  of  the  ends  of  the  sensory 
nerves. 

Temperature. — The  dilatation  of  the  skin  vessels  promotes 
sweating  and  allows  more  blood  to  come  to  the  surface  of  the 
body  to  be  cooled,  so  the  drug  tends  to  lower  temperature  in 
fever  and  to  lessen  internal  congestion  (hence  its  use  internally 
in  colds).  But  camphor  is  not  a  strong  antipyretic. 

Genito-urinary. — It  is  said  to  be  aphrodisiac,  but  there  is 
just  as  much  evidence  that  it  is  anaphrodisiac.  As  a  matter  of 
fact,  the  powerful  psychic  factors  brought  to  play  in  sexual 
manifestations  render  it  very  difficult  to  judge  of  the  effect  of  a 
drug  in  this  field. 

Secretions. — All  tend  to  be  slightly  increased,  the  sweat  and 
mucus  particularly.  This  is  of  too  little  degree,  however,  to  be 
of  use  in  medicine. 

Elimination. — In  the  urine,  combined  with  glycuronic  acid, 
also  in  the  sweat  and  feces,  and  perhaps  in  the  bronchial  mucus. 

Toxicology. — There  have  been  a  number  of  deaths  from  cam- 
phor. The  symptoms  are  those  of  cerebral  stimulation,  viz., 
intellectual  and  motor  activity,  great  excitement,  even  to  ma- 
niacal delirium,  and  epileptiform  convulsions.  This  stage  is 
followed  by  collapse,  coma,  and  death.  The  treatment  is 
whisky  and  bromides. 

Some  years  ago,  while  a  medical  student,  I  came  across  a  case 
of  death  in  a  child  of  two  years  from  one  teaspoonful  of  spirit  of 
camphor,  i.  e.,  6  grains  (0.4  gm).  Recently  one  of  my  female 
patients  took  a  tablespoonful  of  the  spirit  of  camphor,  i.  e.,  24 


CAMPHOR  217 

grains  (1.6  gm.)  of  camphor,  and  became  wide  awake  and  excited 
and  had  real  intellectual  stimulation,  as  if  she  had  taken  strong 
coffee.  Motor  activity  was  not  pronounced,  but  for  several 
hours  there  was  a  sense  of  loss  of  power  in  the  legs.  The  alcohol 
present,  which  was  as  much  as  in  one  ounce  of  whisky,  possibly 
served  as  an  antidote  and  prevented  more  marked  effects.  It 
may  indeed  have  been  the  cause  of  the  sensation  of  diminished 
power  in  the  legs.  Austregesillo  reports  convulsions  in  5  cases 
from  doses  of  10  to  22  grains  (0.6-1.5  gm-)-  Barker  reports  the 
death  of  a  female  child,  sixteen  months  old,  after  swallowing 
probably  |  ounce  of  camphorated  oil  (48  grains  of  camphor), 
some  of  which  was  vomited.  Heard  and  Brooks  report  the 
injection  of  50  grains  (3.3  gm.)  in  oil  without  toxic  mani- 
festations. 

Therapeutics.- — Locally,  it  may  be  employed — (i)  .4$  a 
counterirritant.  Camphorated  oil  is  a  very  weak  preparation, 
but  may  be  used  for  children.  It  is  rubbed  into  the  skin  in  pain 
or  inflammation  of  the  chest  and  throat,  and  in  neuralgic  and 
muscular  pains.  For  adults  the  camphorated  oil  may  be  mixed 
with  an  equal  quantity  of  the  oil  of  turpentine.  Menthol-cam- 
phor and  choral-camphor  are  strong  liquids  which  are  employed 
in  toothache,  neuralgia,  and  muscular  and  joint  pains.  (2)  ./Is 
a  cooling  application — the  spirit  is  applied  in  headache  and  in 
itching  and  erythema  of  the  skin.  It  acts  as  an  evaporating 
liniment.  (3)  As  a  stimulant  and  antiseptic  to  mucous  mem- 
branes in  catarrh  of  nose  and  throat.  It  may  be  added  to  oily 
sprays,  or  used  by  inhalation.  (4)  As  a  carminative  in  flatulence 
or  colic  (spirit  or  water).  (5)  As  anti-diarrheic  (spirit,  or  pills 
of  camphor  and  opium). 

Systemically,  it  may  be  employed — (i)  In  colds,  to  lessen 
internal  congestion  and  fever.  (2)  As  an  antipyretic  in  fever 
mixtures  (as  camphor  water).  (3)  To  overcome  nervous  insta- 
bility and  hysteric  conditions.  (4)  Possibly  as  an  emergency 
circulatory  stimulant  in  collapse  or  shock.  (5)  In  pneumonia, 
Seibert  (1913)  recommends  hypodermatic  doses  of  i  c.c.  of  a 
30  per  cent,  camphorated  sesame  oil  for  each  10  pounds  of  body 
weight.  He  precedes  the  dose  with  2  per  cent,  cocaine  and  re- 
peats it  every  eight  or  twelve  hours. 

Administration. — For  carminative  or  systemic  effects,  the 
water  or  the  spirit,  the  latter  being  dropped  on  a  lump  of  sugar. 

For  diarrhea  the  preferred  preparations  are  Squibb's  Diarrhea 
Mixture,  Sun  Cholera  Drops,  and  Camphor  and  Opium  Pills — 
camphor,  2  grains  (0.13  gm);  opium,  i  grain  (0.06  gm.). 

As  a  circulatory  stimulant  it  is  employed  hypodermatically 
in  solution  in  alcohol,  ether,  or  oil  (camphorated  oil  is  a  20  per 


2l8  PHARMACOLOGY   AND   THERAPEUTICS 

cent,  solution  in  cottonseed  oil).     These  solutions  are  irritant  to 
the  tissues. 

AMMONIUM 

The  ammonium  radicle  (NH4)  is  of  dual  nature,  for,  on  the 
one  hand,  it  is  strongly  alkaline  and  forms  salts  homologous  with 
those  of  the  alkali  metals,  K,  Na,  Li;  and,  on  the  other  hand,  it 
can  liberate  the  irritating  ammonia  gas  (NH3)  from  its  com- 
pounds. From  a  medical  point  of  view,  it  thus  forms  two  series 
of  compounds — those  whose  action  depends  upon  free  ammonia, 
and  those  which  act  as  salts  in  the  body.  Those  which  act  as 
salts  may  be  conveniently  considered  as  of  three  distinct  types, 
according  to  their  therapeutic  uses,  viz.:  (a)  the  chloride;  (b) 
the  acetate;  (c)  the  salts  in  which  the  NH4  ion  is  of  less  impor- 
tance than  the  other  ions.  We  shall  take  up  the  preparations 
according  to  this  classification. 

I.  Those  Whose  Action  Is  Dependent  Upon  Free  Ammonia 

These  include  preparations  of  the  gas  itself,  of  the  hydroxide, 
and  of  the  carbonate. 

Preparations. — i.  Stronger  water  (aqua  ammonige  fortior), 
containing  28  per  cent,  by  weight  of  NH3  gas — not  used  inter- 
nally. 

2.  Water  (aqua  ammoniac,  spirit  of  hartshorn),  10  per  cent., 
7.5  minims  (0.5  c.c.). 

3.  Aromatic  spirit  (spiritus  ammoniae  aromaticus),  9  per  cent, 
of  ammonia  water  and  3.4  per  cent,  of  carbonate,  with  the  aro- 
matic oils  of  lemon,  lavender  flowers,  and  nutmeg.     Dose,  30 
minims  (2  c.c.). 

4.  Liniment  (35  per  cent,  of  ammonia  water  with  cottonseed 
oil),  for  external  use  only. 

5.  Ammonium  carbonate — a  mixture  of  acid  ammonium  car- 
bonate,  NH4HCO3,   and  ammonium  carbamate,  NH4NH2CO2. 
It  is  wholly  soluble  in  4  parts  of  water,  but  the  carbamate  por- 
tion alone  is  soluble  in  alcohol.     It  is  decomposed  by  hot  water. 
It  can  yield  over  30  per  cent,  of  ammonia  gas,  but  it  gives  this 
off  more  slowly  than  do  the  liquid  preparations,  so  is  less  active. 
Dose,  3  grains  (0.3  gm.). 

All  these  preparations  liberate  strong  ammonia  vapor,  and 
in  consequence  are  locally  irritating  and  strongly  antacid.  For 
internal  use  all  should  be  well  diluted. 

Pharmacologic  Action. — The  Skin. — Ammonia  water,  and 
much  more  so  the  stronger  water,  is  strongly  counterirritant. 
It  is  capable  of  producing  not  only  a  rubefacient  effect,  but  more 
marked  degrees  of  irritation,  as  shown  by  the  formation  of  ves- 


AMMONIUM  219 

icles  (vesicant  effect)  or  of  blisters  (epispastic  effect).     Or  it 
may  cause  destruction  of  the  tissue  (caustic  effect) . 

Mucous  Membranes. — All  the  preparations  are  irritant. 
Ammonia  gas  is  extremely  irritating  to  eyes,  nose,  and  respiratory 
passages,  and  its  sudden  inhalation  may  cause  a  momentary 
cessation  of  breathing,  with  shedding  of  tears  and  great  dis- 
comfort. 

Alimentary  Tract. — The  preparations  are  irritant  to  mouth, 
throat,  and  stomach,  and  should  be  well  diluted  before  admin- 
istration. They  are  carminative  and  strongly  antacid,  and  if 
given  during  the  digestive  period,  may  neutralize  the  hydro- 
chloric acid  of  the  gastric  juice,  with  the  formation  of  ammonium 
chloride.  Being  alkaline,  they  also  tend  to  liquefy  mucus. 

Absorption. — Ammonia  gas,  when  inhaled,  is  only  slightly 
absorbed,  but  the  liquid  preparations  are  rapidly  taken  up  from 
the  stomach  or  intestines,  and  unless  changed  to  chloride  by  the 
acid  in  the  stomach,  appear  in  the  portal  blood  as  the  carbonate 
or  carbamate. 

As  ammonia  is  a  regular  constituent  of  the  alimentary  prod- 
ucts, and  as  the  carotid  blood  contains  only  2  to  3  mg.  of  NH3  in 
100  c.c.,  while  the  portal  blood  contains  4  to  6  mg.,  and,  during 
digestion,  even  8  mg.,  per  100  c.c.,  it  is  evident  that  there  is  a 
certain  body  mechanism  for  the  disposal  of  alimentary  ammo- 
nium. It  might  be  well,  therefore,  to  ask  ourselves  what  be- 
comes of  ammonia  given  by  mouth  as  medicine. 

If  ammonium  carbonate  is  administered  by  mouth  to  an 
animal,  there  is  no  increase  of  NH3  in  the  urine,  but  a  propor- 
tional increase  in  urea.  Asher  injected  the  carbonate  and  the 
tartrate  of  ammonium  into  the  portal  veins  of  fasting  dogs,  and 
found  that  the  lymph  in  the  thoracic  duct  contained  more  urea 
than  before,  the  urea  evidently  coming  from  the  liver.  Bain- 
bridge,  with  similar  experiments,  was  unable  to  confirm  Asher 's 
results;  but  Weintraud,  on  administering  up  to  9  grams  of  am- 
monium carbonate  by  mouth,  found  no  increase  in  the  urinary 
excretion  of  ammonia,  but  regularly  an  increase  in  the  urinary 
urea  proportional  to  the  ammonia  administered;  and  this  was 
in  hepatic  cirrhosis,  where  the  liver  was  partly  impaired.  In 
other  cases  of  hepatic  insufficiency  due  to  various  liver  diseases 
more  ammonia  and  a  proportionate  diminution  in  the  urea,  as 
compared  with  cases  with  normal  livers,  have  been  found  in  the 
urine. 

If  ammonium  carbonate  is  added  to  defibrinated  blood  used 
to  perfuse  a  recently  excised  mammalian  liver,  the  urea  in  the 
emerging  blood  is  increased  200  or  300  per  cent.,  and  ammonium 
carbonate  decreases  correspondingly  (Starling).  In  a  dog  the 


220  PHARMACOLOGY   AND   THERAPEUTICS 

liver  may  be  experimentally  side-tracked  by  diverting  the  blood 
from  the  portal  vein  by  a  cannula  to  the  renal  vein  or  by  an  Eck 
fistula,  and  tying  the  portal  vein  to  keep  its  blood  out  of  the  liver. 
The  result  of  this  is  that  more  ammonia  and  less  urea  are  regu- 
larly found  in  the  urine,  the  urine  becomes  alkaline,  and  the 
animal  goes  into  a  state  of  vomiting,  thirst,  muscular  weakness, 
ataxia,  and  stupor,  followed  by  cerebral  excitement,  convulsions, 
coma,  and  death  in  twelve  to  twenty-four  hours.  These  are  the 
symptoms  which  result  when  ammonia  is  injected  directly  into 
the  circulation.  In  these  cases  the  carotid  blood  contains  three 
or  four  times  the  normal  amount  of  ammonia,  or  about  the  same 
proportion  as  in  the  portal  blood. 

It  is  evident,  then,  that  the  liver  is  an  important  factor  in 
the  disposal  of  ammonia,  and  that  if  the  liver  is  functionating 
properly,  it  can  effectually  prevent  the  passage  of  ammonia 
from  the  alimentary  tract  to  the  systemic  circulation.  It  does 
this  by  changing  the  ammonia  to  urea,  the  changes  being  repre- 
sented by  the  following  formulae : 

1.  NH4HCO3.NH4NH2C02  =  3CO(NH2)2  +  CO2  +  sHzO 
Commercial  ammonium  Urea 

carbonate 

2.  NH4NH2CO2  =  CO(NH2)2  +  H2O 
Ammonium  Urea 
carbamate 

3.  (NH4)2CO3      =  CO(NH2)2  +  2H2O 
Neutral  ammo-  Urea 
nium  carbonate 

It  becomes  a  question,  then,  whether  any  of  the  ammonium 
hydroxide  or  carbonate  administered  by  mouth  gets  through  the 
liver  without  being  changed  to  urea.  If  all  the  ammonia  is 
changed,  then  no  ammonia  gets  into  the  circulation  to  exert  a 
systemic  action,  and  the  only  effects  of  these  ammonia  prepara- 
tions taken  by  mouth  must  be  the  local  and  reflex  ones.  It  is 
possible,  of  course,  that  some  of  the  ammonia  gets  through  the 
liver  without  change,  or  passes  into  the  circulation  by  way  of 
the  lymphatics  without  immediately  entering  the  liver,  and  so 
exerts  its  systemic  effects  before  it  is  changed  to  urea.  If  any 
escapes  the  liver,  it  is  probably  changed  to  urea  by  the  muscles. 
Some  of  it  is  absorbed  as  ammonium  chloride,  which  it  forms 
with  the  hydrochloric  acid  of  the  gastric  juice. 

Ammonium  carbonate  administered  hypodermatically  es- 
capes the  liver  for  a  time,  and  exerts  a  strong  systemic  poisonous 
action;  but  even  when  it  is  administered  in  this  way,  it  is  soon 
changed  to  urea  by  the  muscles  and  liver. 

Nervous  System. — Following  the  inhalation  of  the  gas  or  the 


AMMONIUM  221 

swallowing  of  the  preparations,  there  is  an  immediate  reflex  stimu- 
lation of  the  vasoconstrictor  and  respiratory  centers  in  the 
medulla,  and  perhaps  of  the  vagus  or  the  accelerator  centers. 
This  effect  is  evidently  reflex,  from  the  surface  irritation;  for  it 
is  almost  instantaneous,  and  manifests  itself  before  the  drug  can 
be  absorbed.  This  prompt,  though  ephemeral,  reflex  stimulation 
is  taken  advantage  of  to  relieve  mild 'collapse,  as  in  fainting  or 
feelings  of  faintness.  If  the  drug  is  absorbed  into  the  systemic 
blood-stream,  as  when  administered  intravenously,  and  perhaps 
when  given  hypodermatically,  there  is  a  direct  stimulation  of 
the  vagus  and  vasoconstrictor  centers.  There  is  also  increased 
irritability  of  brain  and  cord,  so  that  after  large  doses  there  may 
be  convulsions  like  those  from  strychnine,  followed  by  coma  and 
death. 

Circulatory  Organs.— The  immediate  result  of  the  reflex 
effect  upon  the  vagus,  vasoconstrictor,  and  accelerator  centers 
is  a  rise  in  arterial  pressure,  though  the  rate  of  the  heart  is  vari- 
able, according  as  vagus  stimulation  predominates,  or  accelera- 
tor. After  absorption,  as  from  hypodermic  dosage,  there  is 
slight  direct  stimulation  of  the  vasoconstrictor  and  the  vagus 
centers  and  of  the  heart  muscle,  so  that  arterial  pressure  is 
raised ;  but,  owing  to  the  rapid  change  of  the  drug  in  the  system, 
this  is  of  short  duration.  Very  large  doses  depress  the  heart 
muscle  at  once,  or  after  a  brief  period  of  stimulation. 

The  whole  action  is  so  brief  that  ammonia,  whether  inhaled 
or  given  by  mouth  or  hypodermatically,  is  of  use  as  a  circulatory 
stimulant  only  momentarily,  and  it  has  its  great  value  in  just 
those  passing  depressions  of  the  circulation  which  show  in  feel- 
ings of  faintness  or  fainting. 

Respiratory  System. — A  strong  inhalation,  or  a  concentrated 
dose  by  mouth,  will  stop  the  respiration  for  a  moment;  and  this 
is  followed  by  a  reflex  stimulation  of  the  respiratory  center  from 
the  local  irritation.  If  the  drug  is  absorbed,  there  is  a  direct 
stimulation  of  the  center.  So,  in  any  case,  breathing  is  deepened. 

When  taken  by  mouth,  the  bronchial,  nasal,  and  throat 
mucus  are  believed  to  be  rendered  more  fluid,  and  for  this  reason 
the  carbonate  is  used  in  cough  mixtures.  But,  as  noted  above, 
the  carbonate  is  in  all  probability  changed  either  to  the  chloride 
or  to  urea,  hence  it  does  not  act  by  its  alkaline  property  to  fluidify 
the  mucus.  In  addition,  ammonia  is  not  excreted  by  the  lungs 
(Magnus)  or  in  the  bronchial  mucus,  for  after  the  administration 
it  has  been  found  neither  in  the  bronchial  mucus  nor  in  the  ex- 
pired air  (Mayr).  The  probability  is  that  if  unchanged  in  the 
stomach  it  has  a  nauseant  action,  and  acts  reflexly  to  increase  and 
fluidify  the  bronchial  secretions.  In  those  cases  in  which  it  is 


222  PHARMACOLOGY   AND   THERAPEUTICS 

changed  to  the  chloride  it  may  be  excreted  by  the  bronchial 
glands.  (See  Ammonium  Chloride.) 

Secretions. — As  just  stated,  it  tends  to  loosen  and  fluidify 
mucus.  This  effect  is  especially  to  be  noted  in  the  nose,  throat, 
bronchi,  and  stomach.  Both  urea  and  ammonium  chloride  are 
diuretic. 

Elimination. — The  carbonate  and  hydroxide  are  changed 
to  the  chloride  or  to  urea.  In  the  latter  case  the  excretion  of 
urea  is  increased  without  increase  in  general  metabolism.  The 
blood  is  not  rendered  more  alkaline,  as  it  is  by  the  hydroxides 
and  carbonates  of  the  fixed  alkalies,  and  the  urine  reaction  is 
probably  unaffected. 

Toxicology. — i.  From  Swallowing. — Ammonia  water,  swal- 
lowed undiluted,  causes  great  local  irritation  and  inflammation 
of  mouth,  throat,  esophagus,  and  stomach.  There  may  be  vomit- 
ing. The  inflammation  may  go  on  to  ulceration  or  general 
sloughing;  and,  if  the  patient  recovers,  may  leave  cicatricial 
constrictions  which  wrill  give  trouble  in  after  life.  If  the  burns 
are  very  extensive,  death  may  result  from  shock.  The  ammonia 
fumes  may -get  into  the  larynx  and  produce  edema  of  the  glottis. 
Treatment:  In  the  mouth  or  stomach,  the  poison  may  be  neutral- 
ized by  mild  acids,  such  as  vinegar  or  lemon-juice;  the  pain  and 
inflammation  may  be  lessened  by  bland  oils  or  fats,  such  as 
olive  or  linseed  oil,  lard  or  butter,  or  by  the  white  of  egg,  milk, 
or  demulcent  mucilaginous  drinks. 

2.  From  Inhalation. — Strong  ammonia  fumes  inhaled,  as 
from  the  escape  of  the  gas  in  ice-plants,  or  when  the  liquid  is 
swallowed,  may  cause  swelling  and  inflammation  of  the  larynx 
and  bronchi,  and  through  edema  or  spasm  of  the  glottis  may 
cause  asphyxia  and  death.  The  treatment  is  to  give  plenty  of 
air  or  inhalations  of  oxygen.  If  the  glottis  is  closed  so  as  to 
prevent  breathing,  intubation  or  tracheotomy  should  be  per- 
formed. If  there  is  edema  of  the  glottis,  the  tissues  should  be 
cut  at  once  to  relieve  the  swelling. 

Effects  After  Absorption. — If  the  poison  is  absorbed,  there  may 
be  strychnine-like  convulsions,  collapse,  coma,  and  asphyxia, 
death  being  due  to  paralysis  of  the  respiratory  center  or  to  the 
convulsive  interference  with  breathing.  The  treatment  is 
artificial  respiration,  oxygen,  absolute  repose,  external  heat,  and 
other  treatment  for  collapse  or  convulsions. 

Therapeutics  and  Administration. — i.  As  a  counter  irritant — 
ammonia  liniment  or  ammonia  water.  As  a  blistering-agent  to 
the  gums — ammonia  water. 

2.  As  a  rapid  reflex  circulatory  and  respiratory  stimulant  in 
fainting  or  feelings  of  faintness — ammonia  gas  inhaled  from 


AMMONIUM  223 

ammonia  water  or  smelling  salts;  or  the  aromatic  spirit  of  am- 
monia, taken  by  mouth.  Smelling  salts  are  mostly  made  of 
cakes  of  ammonium  carbonate  covered  with  an  alcoholic  solution 
of  ammonia  containing  aromatic  oils,  such  as  the  oil  of  lavender. 

3.  As  an  antacid  carminative  in  digestive  disturbances  and 
headache,  and  as  a  morning  "pick-me-up"  after  a  debauch— 
the  aromatic  spirit. 

4.  As  an  expectorant  to  fluidify  thick  and  tenacious  mucus 
of  the  respiratory  tract — the  carbonate. 

Contraindication. — Urea  retention,  as  in  nephritis  and  uremia. 

II.  The  Ammonium  Compounds  Which  Are  Not  Dependent 
for  Their  Activity  on  Their  Liberation  of  NH3 

i.  AMMONIUM  CHLORIDE 

The  chloride  or  muriate  of  ammonia  or  sal  ammoniac  (NH4C1) 
has  a  sharply  salty  taste,  and  is  soluble  in  2  parts  of  water  and 
50  of  alcohol.  Dose,  8  grains  (0.5  gm.).  The  only  official 
preparation  is  the  troche  (trochiscus  ammonii  chloridi),  which 
contains  i^  grains  (0.09  gm.)  of  ammonium  chloride  with  sugar, 
licorice,  etc. 

Pharmacologic  Action. — The  chloride  liberates  ammonia  very 
slowly  indeed,  and  is  neither  antacid  nor  caustic. 

Local  Action. — It  has  a  marked  salt  action,  i.  e.,  in  strong 
solution  shrinks  the  tissues  by  abstracting  water,  and  is  irritant. 
In  proper  dilution  it  is  only  slightly  irritant. 

In  the  mouth  it  is  irritant  and  astringent,  causing  shrinkage 
of  the  membranes;  but  in  response  to  the  irritation  there  is  a 
prompt  reflex  flow  of  saliva,  which  serves  as  a  diluent  and 
moistens  the  mouth.  In  the  stomach,  it  is  also  irritant  unless 
well  diluted. 

Absorption. — The  chloride  is  rapidly  absorbed  from  the 
stomach  and  is  not  converted  to  urea  in  the  liver  (Bainbridge). 
(The  sulphate,  in  which  the  ammonium  ion  is  combined  with 
the  non-penetrating  sulphate  ion,  is  not  readily  absorbed  and  is 
consequently  laxative,  but  it  is  not  employed  in  medicine.) 

Its  systemic  action  is  essentially,  if  anything,  to  increase 
secretions,  and  it  has  the  reputation  of  increasing  and  fluidifying 
the  mucous  secretions  of  nose,  throat,  and  bronchi.  Ammonia 
is  not  found  in  the  expired  air,  but  Coleman,  1916,  finds  the  am- 
monia nitrogen  of  the  sputum  increased  from  2  to  5  times  after 
5  grains  (0.03  gm.)  every  two  hours  for  twelve  doses.  He  also 
states  that  the  sputum  tastes  of  ammonium  chloride  and  is  more 
fluid  and  looser.  He  suggests  that  in  passing  through  the  bron- 


224  PHARMACOLOGY   AND   THERAPEUTICS 

chial  wall  the  salt  increases  the  water  of  the  secretion  and  so  les- 
sens the  viscosity  of  the  sputum.  Henderson  and  Taylor  believe 
any  effect  to  be  a  reflex  one,  the  result  of  a  nauseant  action.  (See 
Expectorants.)  By  its  action  as  a  salt  it  may  slightly  increase, 
the  other  secretions,  especially  the  saliva,  the  sweat,  and  the 
urine.  It  is  not  a  circulatory  stimulant,  either  reflex  or  direct. 

Excretion. — Traces  have  been  found  in  several  secretions, 
but  almost  all  of  it  is  excreted  as  ammonium  chloride  in  the 
urine,  the  reaction  of  the  urine  and  the  amount  of  urea  being 
practically  unchanged.  After  175  grains  (5  gm.)  of  ammo- 
nium chloride,  Wolf  and  Osterberg  recovered  52.2  per  cent,  in 
the  urine  in  two  days.  In  bronchitis  it  appears  in  the  sputum 
(Coleman).  It  has  been  calculated  that  the  chloride  ingested 
is  broken  up  in  the  liver  or  in  other  parts  of  the  body  wiih  the 
liberation  of  hydrochloric  acid  and  the  formation  of  urea,  the 
H.C1  thus  set  free  being  immediately  neutralized  and  changed 
back  to  ammonium  chloride  by  NHs  manufactured  by  the  body 
cells;  and  that  it  is  this  freshly  manufactured  chloride  that 
is  excreted.  This  may  be  true,  but  in  any  case,  as  suggested 
by  the  work  of  Bainbridge  on  the  lymph  of  the  thoracic  duct, 
what  leaves  the  liver,  is  the  chloride,  and  ammonia  poisoning 
does  not  result. 

Therapeutics. — For  acute  pharyngitis  the  troches  or  tablets 
may  be  dissolved  ia  the  mouth — a  favorite  remedy  of  the  laity. 
Thus  employed,  the  chloride  is  stimulating  and  astringent,  so  that 
it  causes  a  drawing  up  of  the  relaxed  mucous  membrane,  with  re- 
moval of  its  edematous  state;  it  also  promotes  the  flow  of  saliva, 
so  may  relieve  congestion  and  dryness  of  the  throat.  In  laryngitis 
or  bronchitis  the  drug  is  occasionally  inhaled  as  vapor,  the  vapor 
being  formed  by  exposing  the-chloride  to  heat  or  by  the  admixture 
of  ammonia  and  hydrochloric  acid  gases  in  a  special  apparatus. 
But  its  most  frequent  employment  is  in  cough  mixtures,  to  in- 
crease the  flow  of  mucus  in  the  dry  stages  of  nasal,  throat,  and 
bronchial  inflammations,  i.  e.,  when  the  congestion  is  great 
without  mucous  flow,  or  when  the  mucus  is  thick  and  tenacious. 

2.  AMMONIUM  ACETATE 

The  acetate,  NH4C2H3O2.  is  an  unstable  salt,  and  on  this 
account  is  prepaced  in  solution  when  required.  There  are  two 
official  preparations — the  solution  of  ammonium  acetate  (liquor 
ammonii  acetatis;  spirit  of  mindererus),  and  the  solution  of 
iron  and  ammonium  acetate  (liquor  ferri  et  ammonii  acetatis; 
Basham's  mixture),  the  dose  of  each  of  which  is  2  drams  (8  c.c.). 
The  solution  of  ammonium  acetate  should  be  freshly  prepared,  and 
should  contain  CO..  gas.  It  is  a  palatable,  slightly  salty  prepara- 


TO  INCREASE  THE  BLOOD  IN  THE  ARTERIES       225 

tion,  is  quickly  absorbed,  and  is  changed  to  urea  in  the  liver,  the 
urea  promoting  the  flow  of  urine.  It  may  also  have  a  tendency 
to  increase  the  sweat.  It  is  employed  as  a  refreshing  but  weakly 
acting  diaphoretic  and  diuretic  in  fevers,  especially  those  of 
children.  Basham's  mixture  is  a  palatable  iron  preparation.  As 
it  contains  free  acid,  it  should  be  administered  well  diluted  and 
through  a  tube,  to  protect  the  teeth.  It  is  employed  in  anemic 
conditions  for  its  iron,  and  in  functional  albuminuria  or  chronic 
nephritis  for  both  its  iron  and  its  ammonium  acetate. 

3.  The  other  official  salts  of  ammonium  are  the  bromide, 
iodide,  benzoate,  salicylate,  and  valerate.  In  these  the  effect 
of  the  ammonium  radicle  is  overshadowed  by  the  relatively  more 
potent  acid  radicle,  so  that  these  salts,  except  in  large  doses, 
have  practically  the  action  of  the  potassium  and  sodium  salts  of 
the  same  acids.  They  belong,  pharmacologically,  with  the 
groups  of  bromides,  iodides,  salicylates,  etc. 

MECHANICAL   MEASURES   FOR  RAISING   ARTERIAL   PRESSURE 

In  hemorrhage  or  collapse,  the  immediate  indication  is  to 
restore  the  circulation  of  the  brain  centers,  particularly  of  the 
vasoconstrictor  and  respiratory;  so  mechanical  measures,  to 
increase  the  blood  of  the  trunk,  such  as  raising  the  feet  and 
lowering  the  head,  or  tightly  bandaging  the  limbs,  toes,  or  fingers 
upward,  are  valuable  measures.  By  this  latter  method  the  blood- 
pressure  may  sometimes  be  raised  30  or  40  millimeters  of  mer- 
cury, and  the  bandages  may  be  kept  on  for  half  an  hour  without 
harm  to  the  limbs. 

For  use  in  shock  Crile  has  devised  a  pneumatic  suit,  by  which 
the  surface  pressure  on  the  body  may  be  increased  or  reduced  at 
will.  By  it  he  has  raised  the  arterial  pressure  as  much  as  75  mm., 
and  maintained  the  rise  for  some  time.  To  accomplish  the  same 
purpose,  Meltzer  recommends  bandaging  the  abdomen  and  plac- 
ing weights  upon  it. 

MEASURES  FOR  INCREASING  THE  VOLUME   OF  THE  BLOOD   IN 

THE   ARTERIES 

These  are — (i)  The  transfusion  of  blood;  and  (2)  the  admin- 
istration of  saline  solution  (by  intravenous  infusion,  by  hypo- 
dermoclysis,  or  by  rectal  injection). 

Transfusion  is  the  transmission  of  blood  from  a  vessel  of 
one  person  to  the  vein  or  artery  of  another.  The  blood  of  the 
donor  and  the  recipient  tested  together  must  show  neither  hemol- 
ysis  nor  agglutination,  and  the  donor  must  be  without  trans- 
missible disease,  such  as  syphilis. 
is 


226  PHARMACOLOGY   AND   THERAPEUTICS 

The  direct  method  of  attaching  artery  of  donor  to  vein  of 
recipient  has  been  superseded  by  the  simpler  and  easier  indirect 
methods.  The  first  of  these  to  obtain  wide  recognition  was  the 
syringe-cannula  method  of  Lindemann,  in  which  a  number  of  20 
c.c.  syringes  are  employed  and  a  special  telescopic  cannula  for 
the  vein.  It  permits  the  transference  of  1000  c.c.  in  about  ten 
minutes.  The  Unger  method  requires  but  one  syringe. 

A  simpler  method  still  is  the  use  of  an  anticoagulant,  the 
blood  being  drawn  into  a  sodium  citrate  solution  in  such  propor- 
tion that  it  contains  0.2  per  cent,  of  sodium  citrate,  the  method  of 
Lewisohn  and  others;  or  into  a  vessel  wetted  with  a  solution  of 
hirudin,  the  method  of  Satterlee  and  Hooker. 

These  methods  permit  accurate  measurement  of  the  blood 
transferred,  and  frequent  repetition  of  the  process.  It  is  fur- 
thermore a  simple  matter  to  introduce  saline  into  the  donor's 
blood  to  replace  the  blood  removed.  With  the  anticoagulants 
all  the  apparatus  necessary  is  a  mixing  vessel,  a  vein  needle,  and 
a  funnel  or  fountain  syringe  with  connecting  rubber  tube. 

Transfusion  of  blood  has  advantages  over  saline  infusion, 
for  the  new  blood  supplies  nutritive  material,  oxyhemoglobin, 
and  perhaps  antibodies  or  antitoxins.  Moreover,  blood  is  not 
so  quickly  transuded  out  or  excreted  as  a  salt  solution  would 
be;  consequently  it  tends  to  maintain  the  increased  arterial 
pressure  for  a  longer  time.  In  hemorrhage  transfusion  may  result 
in  increased  coagulability  of  the  blood. 

Levin  has  made  a  comparative  study  of  the  ability  of  saline 
solutions  and  transfused  blood  to  replace  blood  lost  by  hemor- 
rhage. In  a  number  of  dogs  he  let  out  enough  blood  to  kill,  i.  e., 
about  4.5  to  5.5  per  cent,  of  the  body  weight,  and  allowed  the 
heart  to  come  to  a  standstill.  On  replacing  the  blood  with  saline 
the  heart  began  to  beat  again  for  a  time,  but  the  animal  did  not 
revive.  On  replacing  the  lost  blood  with  fresh  blood  by  trans- 
fusion, the  heart  began  to  beat  again,  and  usually  in  as  little  as 
five  minutes  this  resulted  in  the  dog's  return  to  just  as  good 
condition  as  before  the  experiment. 

Therapeutics. — i.  Collapse  or  shock  from  any  cause,  but 
especially  when  there  is  hemorrhage.  In  the  acute  hemorrhages 
the  safest  guide  is  the  blood-pressure,  a  pressure  down  to  70 
indicating  transfusion  (Bernheim). 

2.  Profound  anemia  of  any  type.  In  the  chronic  bleedings 
and  anemias  the  guide  is  the  hemoglobin,  transfusion  being  indi- 
cated at  40  per  cent,  if  the  hemoglobin  is  progressing  downward 
(Bernheim). 

In  many  cases  of  shock,  hemorrhage,  or  profound  anemia  a 
preliminary  transfusion  may  permit  necessary  surgery.  In 


TO   INCREASE    THE    BLOOD   IN   THE    ARTERIES  227 

pernicious  anemia,  for  example,  it  is  the  practice  to  transfuse  both 
before  and  after  splenectomy. 

3.  Hemophilia,  especially  before  an  operation,   or    in    the 
presence  of  hemorrhage.     In  several  cases  Lindemann  reports 
persistence  of  increased  coagulability  for  many  months. 

4.  Profound  malnutrition  and  the. psychoses  of  inanition. 

5.  Protracted  weakness  or  prostration. 

6.  In  infectious  conditions,  such  as  malignant  endocarditis 
or  any  form  of  sepsis,  the  blood  of  an  immune  donor,  i.  e.,  one 
who  has  had  such  an  infection  and  recovered,  or  one  treated  by 
vaccines  made  from  the  germ  involved,  has  been  tried,  in  a  few 
cases  with  seemingly  good  results.     It  has  failed  to  help  in 
typhoid  fever. 

(Defibrinated  blood  was  formerly  employed  in  some  instances, 
but  the  process  of  defibrination  introduces  possibilities  of  infec- 
tion and  is  decidedly  disadvantageous.) 

Saline  Infusion. — Intravenous  infusion  requires  a  graduated 
reservoir  for  the  saline,  a  rubber  tube  for  transmission  of  the 
liquid,  and  a  cannula  or  nozzle  (the  glass  portion  of  an  eye-dropper 
or  a  vein-needle  will  do)  for  insertion  into  the  vein.  The  amount 
administered  is  from  500  to  1500  c.c.  (about  i  to  3  pints),  quan- 
tities much  above  this  being  contraindicated,  as  noted  below. 

The  solutions  employed  for  infusion  are: 

1.  Normal  saline  (liquor  sodii  chloridi  physiologicus)  which 
contains  0.85  per  cent,  of  sodium  chloride,  about  a  full  teaspoon 
to  one  pint  (for  frogs  normal  saline  is  of  0.7  per  cent,  strength). 
This  is  the  most  universally  employed  infusion  fluid;  but,  because 
of  the  absence  of  all  other  salts,  especially  those  of  potassium 
and  calcium,  which  are  required  by  the  tissues  and,  according  to 
Jacques  Loeb,  prevent  sodium  chloride  poisoning,  and  because  its 
reaction  is  not  alkaline,  it  is  not  by  any  means  the  best  solution. 
Indeed,  normal  saline  is  better  made  from  hard  drinking-water, 
which  contains  calcium,  than  from  distilled  water.     For  pure 
sodium  chloride  intravenously  is  poisonous,  and  normal  saline 
made  from  distilled  water  may  have  a  veratrine  action  upon 
muscle,  i.  e.,  it  may  cause  increased  contraction  with  retarded  re- 
laxation; while  if  the  slightest  amount  of  calcium  salt  is  present, 
the  chance  of  this  action  is  avoided.     Ordinary  table  salt  regularly 
contains  some  calcium.     The  0.7  per  cent,  saline  is  not  to  be 
employed,  for  in  some  hemolytic  conditions  the  blood  has  been 
found  to  hemolyze  with  this  strength  saline. 

2.  Dawson's  solution — 0.8  per  cent,  of  sodium  chloride  with 
0.5  per  cent,  of  sodium  bicarbonate. 

3.  Locke  s  solution — the  best  of  all.     Its  formula  is:  Sodium 
chloride,  0.9  gm. ;  potassium  chloride,  0.042  gm. ;  calcium  chloride, 


228  PHARMACOLOGY  AND  THERAPEUTICS 

0.0024  gm.;  sodium  bicarbonate,  0.03  gm.;  dextrose,  o.i  gm.;  and 
distilled  water,  a  sufficient  quantity  to  make  100  c.c.  This 
contains  the  necessary  salts,  and  is  alkaline  and  nutritive. 

4.  The   Ringer-Locke  solution — Locke's,   with   the   dextrose 
omitted. 

5.  Ringer's  solution,  much  used  in  the  laboratory,  contains 
the  chloride  of  sodium,  0.7  per  cent.,  with  the  chlorides  of  potas- 
sium and  calcium.     It  was  especially  designed  for  frogs  and 
turtles. 

To  understand  the  effects  of  saline  solutions  in  the  body  we 
must  know  what  is  meant  by  the  physiologic  terms  filtration, 
diffusion,  and  osmosis,  and  the  nature  of  hy polemic  (hypoisotonic) , 
isotonic,  and  hypertonic  (hyperisotonic)  solutions.  These  are 
well  explained  in  any  modern  physiology,  such  as  Schafer,  Star- 
ling, or  Howell. 

In  infusion,  a  large  quantity  of  liquid  is  passed  into  the  circu- 
lation; it  should,  therefore,  be  practically  isotonic  with  the  blood. 
If  a  hypertonic  liquid  is  employed,  i.  e.,  a  liquid  containing  too 
large  a  proportion  of  salts,  the  blood  abstracts  water  from  the 
tissues  and  swells  in  volume,  to  become  still  more  dilute  than 
the  amount  of  injected  liquid  alone  would  make  it;  a  greatly 
hypertonic  liquid  will  injure  the  blood-cells.  On  the  other  hand, 
a  hypo  tonic  liquid  will  tend  to  lake  the  blood ;  outside  the  body  a 
solution  of  0.4  to  0.44  per  cent,  of  sodium  chloride  will  do  this 
normally. 

The  effects  of  a  saline  infusion  differ  according  to  whether 
the  volume  of  blood  has  been  previously  decreased  or  not;  there- 
fore must  be  considered  from  these  two  points  of  view. 

i.  When  the  Volume  of  the  Blood  Has  Not  Been  Decreased  by 
Hemorrhage  or  Other  Cause. — In  normal  animals  the  tendency  of 
the  blood  to  regain  its  normal  condition  is  so  pronounced  that 
almost  as  soon  as  an  infusion  is  begun  the  mechanisms  for  regula- 
tion are  started.  As  the  result  of  increased  pressure  in  the  capil- 
laries there  is  an  immediate  outpouring  of  weak  lymph,  and  this 
is  followed  by  elimination  of  liquid  through  the  intestines  and 
kidneys  (Starling),  so  that  in  half  an  hour  not  only  will  the  vol- 
ume of  the  blood  have  returned  to  normal,  but  its  constituents 
will  have  regained  their  proper  relative  proportions  (Crile). 

In  experimenting  with  saline  infusions  in  61  normal  dogs, 
Crile  found  that,  besides  the  rapid  transudation  of  lymph,  there 
was  a  dilatation  of  the  splanchnic  arterioles,  so  that  most  of  the 
extra  volume  of  blood  was  received  in  the  splanchnic  area  with- 
out raising  the  general  arterial  pressure;  thence  it  was  rapidly 
excreted  by  the  kidneys  and  intestines.  Both  on  account  of 
this  sensitive  vasomotor  mechanism  and  of  the  active  capillary 


TO   INCREASE   THE   BLOOD   IN   THE    ARTERIES  22Q 

transudation,  he  was  unable  to  get  a  rise  in  the  arterial  pressure 
of  more  than  8  mm.  of  mercury,  even  from  enormous  amounts  of 
saline.  Indeed,  the  mechanisms  for  keeping  the  blood  normal 
proved  so  active  that  after  a  certain  dilution  of  the  blood  was 
reached  it  was  practically  impossible  to  bring  about  further 
dilution,  and  the  only  result  of  further  infusion  was  to  produce 
general  edema.  The  limit  of  safe  dosage  he  ascertained  to  be 
30  c.c.  of  saline  per  kilo  of  body  weight,  which  in  the  same  ratio 
would  be  about  2200  c.c.  for  a  i6o-pound  man.  Clinical  experi- 
ence favors  smaller  amounts  for  man,  and  has  proved  the  danger 
of  such  large  quantities. 

So  when  the  volume  of  blood  is  already  normal,  the  addition 
of  saline  solution  has  only  a  transitory  mild  effect  on  arterial 
pressure,  and  chiefly  increases  urination  and  the  tendency  to 
edema.  It  tends  also  to  lessen  the  viscosity  of  the  blood,  but 
this  action  is  so  ephemeral  that  it  probably  has  very  little  influ- 
ence on  the  blood-stream. 

Crile  found,  further,  that  the  dilution  of  the  blood  does  not 
prevent  the  action  of  circulatory  stimulants;  that  if  vasocon- 
strictor stimulants  were  administered  at  the  same  time  as  the 
saline,  the  arterial  pressure  could  be  raised  above  normal  for  a 
time;  but  that,  when  the  splanchnic  arteries  were  excluded,  the 
dilution  of  the  blood  increased  so  rapidly  with  the  progress  of  the 
infusion  that  edema  set  in  very  quickly,  even  though  the  arterial 
pressure  was  not  essentially  raised.  This  indicates  that  if,  by 
a  strong  vasoconstrictor,  such  as  epinephrine,  dilatation  of  the 
splanchnic  arteries  is  prevented,  the  chances  of  edema  are  in- 
creased. Hence  in  intravenous  infusion,  since  the  liquid  must 
pass  to  the  right  heart  and  to  the  lungs  first,  pulmonary  edema  is 
favored;  and  especially  is  this  the  case  if  at  the  same  time  there 
is  marked  back  pressure  on  the  left  heart  from  constriction  of 
the  peripheral  arterioles.  Therefore,  as  might  be  expected,  pul- 
monary edema  is  especially  readily  brought  about  by  a  combina- 
tion of  saline  infusion  and  epinephrine. 

Summary. — When  the  volume  of  the  blood  has  not  been 
reduced,  saline  infusion  to  raise  arterial  pressure  is  almost  useless, 
and  by  producing  edema,  may  have  serious  consequences.  If 
used  as  a  medium  for  the  administration  of  drugs,  it  should  be 
employed  in  small  quantity,  and  slowly  introduced.  By  trans- 
fusion of  blood,  on  the  contrary,  it  has  been  found  possible  to 
raise  arterial  pressure  away  above  the  normal,  and  to  maintain 
it  there  for  some  little  time. 

2.  When  the  Volume  of  the  Blood  is  Notably  Below  Normal,  as 
After  a  Large  Hemorrhage. — From  25  to  50  per  cent,  of  an  animal's 
blood  may  be  removed  and  replaced  with  saline  without  serious 


230  PHARMACOLOGY   AND   THERAPEUTICS 

results  (Levin).  Crile  noted  that  after  a  moderate  hemorrhage 
a  saline  infusion  would  increase  the  volume  of  the  blood  so  that 
normal  arterial  pressure  would  be  maintained  for  a  considerable 
period.  He  found  also  that  the  blood  has  a  shorter  coagulation 
time,  the  saline  thus  favoring  the  cessation  of  the  hemorrhage. 
So  saline  infusions  are  valuable  to  replace  lost  blood,  and  may  be 
used  with  advantage  whether  the  bleeding  has  stopped  or  not. 

A  few  further  observations  of  Crile  on  the  effects  of  infusions 
are  worth  mentioning:  The  temperature  of  the  infusion,  if  within 
reasonable  limits,  makes  almost  no  difference,  either  in  the  tem- 
perature of  the  patient  or  in  the  heart-beat.  The  rate  of  flow 
makes  no  difference  in  the  extent  of  the  effect  on  arterial  pressure. 
The  effect  on  respiration  is  an  increase  in  frequency  and  depth; 
but  "from  greater  than  safe  amounts  the  breathing  becomes 
slowed,  and  there  regularly  ensue  edema  of  the  lungs  and  death 
from  respiratory  failure." 

Therapeutics. — i.  In  hemorrhage — to  restore  the  blood  vol- 
ume to  normal  and  thus  permit  the  maintenance  of  arterial 
pressure.  Probably  not  over  1200  c.c.  should  be  given  at  one 
time.  Bernheim  cites  a  case  of  exsanguination  in  which,  after 
2000  c.c.  of  saline,  salt  solution  instead  of  blood  flowed  from  the 
incision  made  for  transfusion.  He  advises  that  with  saline  if 
there  is  a  fall  in  blood-pressure  after  a  preliminary  rise  further 
saline  is  dangerous. 

2.  In  cholera — to  restore  the  volume  of  the  blood  and  supply 
liquid  to  the  tissues.     Rogers  has  found  a  hypertonic  fluid  best, 
as  it  checks  the  transudation  of  fluid  into  the  intestines. 

3.  In  toxemic  conditions — to  promote  kidney  activity,  with 
the  idea  of  carrying  out  the  poison.     In  uremia,  saline  infusion  is 
sometimes   employed   after   considerable   blood-letting,    though 
ordinarily  in  kidney  cases  the  saline  is  given  by  rectum  instead  of 
intravenously.     If  there  is  salt  retention,  sodium  bicarbonate  or 
potassium  acetate  may  be  substituted  for  the  sodium  chloride. 
Levin  considered  bleeding  followed  by  infusion  a  useless  procedure 
in  toxemic  conditions,  for  he  could  obtain  no  appreciable  effect 
from  it  in  artificially  produced  toxemias.     In  strychnine  poison- 
ing Delbert  has  prevented  toxic  symptoms  by  the  use  of  saline 
infusion. 

4.  In  severe  collapse  or  shock — a  small  saline  infusion  of  about 
500  c.c.,  given  slowly  and  containing  epinephrine  or  pituitary 
liquid,  may  promote  the  maintenance  of  blood-pressure.     A  large 
infusion  merely  favors  the  production  of  edema.     In  post-opera- 
tive collapse,  the  saline  may  replace  blood  lost  in  the  operation, 
but  care  must  be  used  not  to  administer  too  great  a  quantity. 

Saline  by  Hypodermoclysis  and  Enema. — After  hemorrhage, 


ACONITE  23 1 

absorption  from  the  rectum  is  especially  rapid,  and  one  or  two 
quarts  may  be  given  by  enema  without  expulsion.  Under 
ordinary  conditions,  too,  hot  saline  by  rectum  regularly  shows  a 
prompt  effect  upon  the  kidneys.  Even  by  hypodermoclysis 
over  the  abdomen,  in  the  axillary  line,  in  the  thighs  or  beneath 
the  breasts,  as  much  as  a  pint  (500  c.c.)  of  saline  may  be  used  in 
some  cases  in  about  ten  or  fifteen  minutes,  or  double  this  amount 
in  half  or  one  hour,  During  major  operations  Lane  keeps  up  a 
supply  of  fluid  by  a  needle  in  the  subcutaneous  tissue  of  each 
side  of  the  chest  about  at  the  anterior  axillary  line,  the  so-called 
"axillary  sup." 

Contraindications — any  form  of  edema,  but  especially  that 
of  the  lungs,  and  that  resulting  from  sodium  chloride  retention, 
as  in  nephritis. 

Toxicology. — Chills  and  fever  have  been  reported  following 
saline  infusions.  They  have  been  attributed  to  the  products 
of  dead  bacteria  in  the  water  used.  Several  cases  of  death  have 
occurred  from  the  use,  by  rectum  or  intravenously,  of  concen- 
trated solutions  of  sodium  chloride  in  mistake  for  normal  saline. 
(See  Sodium  Chloride,  under  Alkalies.) 

REMEDIES  WHICH  LOWER  BLOOD-PRESSURE 
These  we  are  able  to  divide  into  three  classes : 

(a)  Cardiac  depressants. 

(b)  Arterial  dilators. 

(c)  Measures  for  decreasing  the  volume  of  blood. 

THE  CARDIAC  DEPRESSANTS 
ACONITE 

Aconitum  (aconite,  monkshood)  is  the  dried  tuberous  root  of 
Aconitum  napellus  (Fam.  Ranunculacea] ,  collected  in  autumn, 
and  yielding  when  assayed  not  less  than  0.5  per  cent,  of  aconitine. 
It  is  a  European  herb,  extensively  cultivated  as  a  garden  flower. 

Constituents. — Several  alkaloids,  of  which  aconitine  is  the 
essential  active  one.  Aconine,  present  in  minute  quantity,  is 
said  to  be  a  cardiac  stimulant,  while  benzaconine,  picraconitine, 
and  aconitic  acid  are  inert. 

Preparations  and  Doses. — The  preparations  on  the  market 
are  exceedingly  variable,  many  of  them  having  been  found 
almost  inert.  They  deteriorate  rapidly  on  keeping.  The 
Pharmacopoeia  requires  a  biologic  assay. 

Aconite,  assaying  not  less  than  0.5  per  cent,  of  ether-soluble 
alkaloids,  i  grain  (0.06  gm.). 

Fluidexlract,  i  minim  (0.06  c.c.). 

Tincture,  10  per  cent.,  10  minims  (0.06  c.c.). 


232  PHARMACOLOGY   AND   THERAPEUTICS 

Aconitine,  dose,  4-^  grain  (0.15  mg.),  is  insoluble,  in  water 
and  soluble  in  oil  or  alcohol.  It  is  one  of  the  most  powerful 
poisons  known.  As  marketed,  it  is  highly  variable,  some 
specimens  having  been  found  a  hundred  times  as  strong  as 
others. 

Pharmacologic  Action. — Skin. — Following  the  application 
to  the  skin  of  an  oily  or  alcoholic  solution  of  aconite  there  are 
tingling,  pricking,  and  smarting  of  the  part.  This  is  not  accom- 
panied by  the  phenomena  of  counterirritation,  i.  e.,  general 
irritation  of  the  tissues,  with  redness  and  warmth,  as  after  am- 
monia or  mustard,  for  aconite  is  not  a  general  protoplasmic 
irritant,  but  a  selective  drug.  The  primary  stimulation  of  the 
nerve-endings  is  followed  by  depression,  which  shows  in  numb- 
ness and  diminished  appreciation  of  pain  and  touch,  i.  e.,  partial 
local  anesthesia.  Since  the  drug  is  highly  selective,  these  effects 
on  nerve-endings  are  also  seen  from  large  doses  of  the  drug  acting 
systemically,  as  when  it  is  administered  by  mouth.  Short  and 
Salisbury  could  get  no  cutaneous  anesthesia  from  a  3  per  cent, 
solution  of  aconitine;  and  it  may  be  that  the  stimulating  effect  is 
the  essential  one. 

Alimentary  Tract. — The  taste  is  bitter,  and  from  even  a  very 
dilute  solution  (i  :  500,000  of  aconitine),  the  mouth,  lips,  and 
tongue  may  feel  a  pricking  and  biting  sensation,  followed  by 
numbness.  The  saliva  is  increased  at  first  largely  reflexly,  as 
the  result  of  the  presence  of  an  offending  substance  in  the  mouth, 
but  partly  from  direct  stimulation  of  the  secretory  nerve-endings; 
these  are  later  depressed,  the  mouth  becoming  dry  from  the 
absence  of  saliva.  Squibb's  test  for  aconite  is  to  hold  i  dram 
(4  c.c.)  of  a  solution  of  i  :  70  of  the  tincture  in  the  anterior  part 
of  the  mouth  for  one  minute,  then  discharge  it.  A  distinct 
tingling  will  be  apparent  in  ten  to  fifteen  minutes. 

In  the  stomach  and  intestines  the  unpleasant  local  action  may 
result  in  nausea,  vomiting,  and  catharsis,  but  such  effects  are 
unusual  from  therapeutic  doses.  After  absorption,  the  vomit- 
ing center  may  show  increased  sensitiveness,  as  from  digitalis; 
but  in  practice  vomiting  is  rare,  for,  unlike  digitalis,  aconite  is 
seldom  employed  in  full  doses  for  long  periods. 

Absorption  is  rapid  through  mucous  membranes.  From 
oily  or  alcoholic  preparations  it  is  also  fairly  rapid  through  the 
skin,  hence  liniments  must  be  employed  with  caution.  The 
drug  causes  too  much  pain  for  hypodermatic  use. 

Circulation. — After  a  very  brief  period  of  increased  activity 
from  accelerator  stimulation,  the  heart  becomes  slowed  through 
prolongation  of  the  diastolic  pause,  and  there  is  diminished 
muscular  contraction  in  systole,  i.  e.,  the  heart  does  less  work  and 


ACONITE  233 

has  a  longer  resting  period,  and  there  is  diminished  output  of 
blood  and  a  gradual  lowering  of  blood-pressure.  This  is  the 
typical  vagus  effect;  and  it  must  be  due  to  stimulation  of  the 
vagus  center,  for  it  does  not  occur  if  the  vagi  are  cut  or  after 
atropine.  This  is  followed  by  the  same  stages  as  result  from 
digitalis. 

As  a  matter  of  fact,  in  laboratory  animals  aconite  produces 
effects  which  resemble  so  closely  those  of  digitalis  that  one  would 
think  of  the  drugs  as  belonging  to  the  same  pharmacologic  class. 
Following  or  accompanying  the  slowing  there  may  be  sinus 
arhythmia,  heart-block,  or  one  or  other  of  the  manifestations 
of  increased  irritability,  normally  inactive  points  in  the  heart 
taking  on  the  power  of  originating  stimuli  (Cushny).  (See 
Digitalis.)  It  was  with  aconite  that  Cushny  discovered  the 
phenomenon  of  reversed  or  retrograde  rhythm,  in  which  the 
auricular  beat  follows  that  of  the  ventricle  instead  of  preceding  it. 
In  toxic  amounts  it  also  constricts  the  arteries  by  stimulation  of 
the  vasoconstrictor  center. 

In  therapeutics  it  has  been  assumed  that  pure  vagus  stimula- 
tion might  be  obtained,  as  shown  by  a  slowing  of  the  rate  and  a 
fall  in  arterial  pressure.  But  Mackenzie  (1911)  gave  tincture  of 
aconite,  beginning  with  5  minims  every  two  hours,  then  10 
minims,  then  15.  Although  the  dose  was  given  for  several  days 
in  many  cases,  not  the  slightest  effect  could  be  detected.  Then, 
at  Cushny's  suggestion,  he  got  Price  to  try  aconitine  in  cases  of 
auricular  fibrillation  in  which  digitalis  proved  effective,  and  in 
cases  of  rapid  heart  due  to  fever  and  other  causes.  Price  care- 
fully pushed  the  drug  until  the  patient  felt  tingling  of  the  tongue 
and  skin,  but  in  not  a  single  instance  did  he  get  any  evidence  of 
a  reaction  on  the  heart  or  blood-vessels.  Rudolf  and  Cole  (1912), 
in  tests  on  55  patients  with  and  without  fever,  failed  to  get  any 
change  in  the  pulse-rate.  They  gave  as  much  as  4^  minims  of 
the  B.  P.  tincture,  equivalent  to  2\  minims  (0.14  c.c.)  of  the 
U.  S.  P.  tincture,  every  ten  to  fifteen  minutes  for  8  to  10  doses. 

On  the  other  hand,  W.  H.  Thomson  (1915)  considers  that  it 
has  a  special  value  in  reducing  the  high  arterial  pressure  in  chronic 
interstitial  nephritis.  He  uses  up  to  10  drops  of  the  35  per  cent, 
tincture,  equivalent  to  35  drops  or  about  18  minims  (i.i  c.c.)  of 
the  U.  S.  P.  tincture.  He  finds  the  excretion  of  urea  greatly 
increased,  and  states  that  both  these  effects  have  been  corrob- 
orated by  J.  E.  Welch.  In  a  verbal  communication,  Welch 
informs  me  that  he  gets  such  results  only  from  large  and  fre- 
quent doses  of  the  strong  tincture. 

Laboratory  experiments  show  that  from  therapeutic  amounts 
there  is  no  depression  of  any  part  of  the  vasoconstrictor  mechan- 


234  PHARMACOLOGY   AND   THERAPEUTICS 

ism;  and  the  drug  lowers  arterial  pressure,  if  at  all,  by  pure 
cardiac  depression  and  not  by  dilatation  of  the  arteries. 

Respiratory.— From  moderate  doses  there  is  stimulation  of 
the  respiratory  center,  with  increased  depth  and  frequency  of 
respiration;  but  from  doses  beyond  therapeutic  there  is  early 
depression  of  the  center,  with  slowing  of  the  respiration,  labored 
breathing,  and  lessening  of  the  intake  of  air.  In  poisoning  there 
may  be  also  some  stimulation  of  the  sensory  vagus  endings  in  the 
lungs  (for  the  accessory  respiratory  muscles  contract  vigorously) , 
and  a  stimulation  of  the  bronchoconstrictor  nerve-endings,  the 
result  being  bronchial  spasm  (Dixon).  Death  takes  place  from 
asphyxia  due  to  paralysis  of  the  respiratory  center.  If  artificial 
respiration  is  maintained,  the  heart  will  continue  to  beat  for 
some  time  after  the  respiratory  center  fails. 

Cerebrum. — This  is  the  last  part  of  the  nervous  system  to  be 
affected,  and  consciousness  is  retained  until  the  final  stages  of 
poisoning.  The  mind  becomes  dulled  only  when  the  patient 
passes  into  collapse. 

Medulla. — The  vagus  center  is  stimulated,  as  already  indi- 
cated; the  vasoconstrictor  center  is  stimulated  by  poisonous  doses, 
but  this  stimulation  soon  passes  into  depression;  the  respiratory 
center  is  at  first  stimulated  but  very  soon  depressed,  and  through 
its  paralysis  death  is  produced.  The  vomiting  center  may  be 
stimulated;  the  heat-regulating  center  may  be  affected  so  that 
temperature  in  fever  is  lowered.  Convulsions  may  occur  in  the 
poisoning,  and  are  due  either  to  asphyxia  or  to  stimulation  of 
the  reflex  centers  of  medulla  and  spinal  cord. 

Peripheral  Nerves. — The  peripheral  ends  of  the  sensory  and 
secretory  nerves  we  have  already  spoken  of.  They  are  strongly 
stimulated,  and  later  depressed.  This  effect  is  observed  not  only 
on  local  application,  but  also  after  the  drug  is  absorbed,  for 
aconite  is  selective.  From  a  poisonous  dose  taken  internally 
the  tingling,  and  later  the  numbness,  become  general.  The 
ends  of  motor  nerves  are  also  somewhat  stimulated  and  later 
depressed.  The  ends  of  the  nerves  conveying  heat  and  cold 
sensations  are  affected  in  the  poisoning,  and  cause  chilly  feelings 
regardless  of  any  changes  in  the  cutaneous  circulation  or  in  the 
body  temperature. 

Muscle. — From  large  amounts  there  is  slight  direct  stimula- 
tion of  cardiac  muscle  (already  referred  to)  and  of  voluntary 
muscle,  as  indicated  by  its  occurrence  after  curare.  This  is  of  no 
therapeutic  importance. 

Temperature. — Aconite  is  antipyretic,  i.  e.,  it  tends  to  induce 
a  fall  of  temperature  in  fever,  but  it  is  not  strongly  so.  There 
seems  to  be  a  stimulation  of  the  heat-regulating  center,  the  cen- 


ACONITE  235 

ter  which  sets  going  the  mechanisms  to  bring  an  abnormal  tem- 
perature to  normal.  (See  Antipyretics.)  The  fall  in  tempera- 
ture results  from  lessened  production  of  heat,  owing  to  dimin- 
ished activity  of  the  circulation,  but  there  is  also  some  increase 
of  heat  loss  from  a  moderate  dilatation  of  the  skin  vessels,  and 
perhaps  from  sweating. 

Secretions. — The  saliva  is  increased,  as  already  mentioned, 
partly  reflexly  from  the  mouth,  and  partly  through  stimulation 
of  the  secretory  nerve-ends.  The  sweat  is  also  increased,  but 
free  sweating  is  irregular  and  not  marked.  It  is  believed  to  be 
due  to  stimulation  of  the  nerve-endings  in  the  sweat-glands,  and 
slightly  to  dilatation  of  the  skin  vessels.  At  best,  aconite  is  a 
mild  and  uncertain  diaphoretic. 

Excretion. — The  active  principles  are  excreted  mostly  in  the 
urine;  traces  have  also  been  found  in  other  secretions,  as  the 
saliva,  gastric  juice,  bile,  and  sweat.  The  kidneys  are  unaffected. 

Toxicology. — Poisoning  from  doses  by  mouth  is  readily 
recognized  by  the  prompt  tingling  of  mouth,  lips,  and  tongue, 
followed  by  numbness.  There  may  also  be  nausea,  vomiting, 
diarrhea,  and  pain  in  the  stomach.  After  absorption  the  tin- 
gling may  become  general  over  the  whole  surface  of  the  body, 
being  first  noticed  in  the  finger-tips.  The  pupil  is  dilated  and 
the  vision  deranged,  with  mistiness  of  the  sight  or  diplopia. 
Early  in  the  poisoning  there  are  the  peculiar  chilly  sensations. 
The  breathing  may  be  asthmatic,  labored,  from  constriction  of 
the  bronchi,  and  there  may  be  cyanosis. 

The  circulatory  changes  we  have  spoken  of.  Blood-pressure 
is  lowered,  then  raised,  then  again  lowered,  and  collapse  follows. 
Death  takes  place  usually  from  asphyxia  caused  by  respiratory 
paralysis,  but  perhaps  also  from  ventricular  fibrillation  or  heart- 
block.  It  takes  about  0.2  mg.  of  aconitine  per  kilo  to  kill  a 
rabbit  (Eden). 

The  treatment  of  poisoning  by  aconite  consists  in  washing  out 
the  stomach,  keeping  patient  in  absolute  repose,  keeping  up 
bodily  heat,  and  treating  the  condition  of  the  heart  as  indicated 
under  Digitalis.  Atropine  is  said  to  be  particularly  antidotal, 
because  it  not  only  checks  vagus  activity,  but  also  stimulates 
the  respiratory  center  and  depresses  the  constrictor  endings  in 
the  bronchial  muscles,  thus  overcoming  the  labored  breathing. 

Therapeutics. — Aconite  is  a  drug  that,  in  the  light  of  recent 
research,  has  doubtful  therapeutic  value.  Externally  it  is  used  in 
liniments  to  allay  pain,  as  in  neuralgia,  lumbago,  and  muscular 
pains.  It  is  applied  to  the  gums  in  toothache.  Internally  its 
value  may  be  considered  problematic.  It  has  been  employed 
extensively  to  slow  and  quiet  a  heart  which  is  overacting  from 


236  PHARMACOLOGY   AND   THERAPEUTICS 

any  cause,  for  example,  in  nervous  excitement  or  in  sthenic 
fevers  with  quick  pulse  and  high  arterial  pressure.  Also  to 
reduce  arterial  pressure  when  very  high,  as  in  chronic  nephritis 
or  convulsive  conditions,  as  uremia  or  eclampsia. 

In  the  fevers  of  children,  and  for  adults  at  the  onset  of  acute 
pharyngitis  or  tonsillitis  or  bronchitis,  aconite  has  been  employed 
empirically.  Its  supposed  beneficial  effects  in  these  cases  have 
been  attributed  to  its  antipyretic  action,  and  perhaps  to  its 
power  to  quiet  the  rapid  heart  and  lower  the  heightened  blood- 
pressure  which  is  associated  with  the  onset  of  a  cold.  It  is  much 
less  used  in  fever  than  formerly. 

It  is  sometimes  administered  internally  in  trifacial  neuralgia, 
with  alleged  relief  of  the  pain. 

Administration. — For  adults,  a  customary  dose  is  3  to  5 
minims  of  the  tincture  given  every  hour  for  three  or  four  doses. 
It  is  frequently  given  in  tablets,  each  representing  3  minims  (0.2 
c.c.)  of  the  tincture.  For  children  the  tincture  may  be  added  to 
the  liquor  ammonii  acetatis  to  make  a  fever  mixture.  It  is  irra- 
tional therapeutics  to  administer  atropine  or  belladonna  at  the 
same  time  as  aconite,  for  atropine  paralyzes  the  vagus  endings 
and  checks  the  vagus  effect  upon  the  heart. 

Delphinium  (larkspur)  and  staphisagria  (stavesacre)  are 
botanic  and  pharmacologic  relatives  of  aconite,  but  they  are 
limited  in  their  therapeutic  use  to  the  destruction  of  pubic  and 
head  lice.  A  mixture  of  equal  parts  of  the  tincture  of  delphinium 
and  ether  is  a  favorite  prescription.  It  should  be  specifically 
labeled  "Poison."  The  poisonous  symptoms  are  the  same  as 
those  of  aconite. 

VERATRUM 

The  dried  rhizome  and  roots  of  Veratrum  viride,  American 
hellebore,  (Fam.  Liliacees),  a  tall  coarse  herb  of  wet  regions, 
growing  in  all  parts  of  North  America. 

Constituents. — There  is  great  confusion  about  the  constitu- 
ents. Veratrine  is  a  term  which  has  been  applied  to  several 
distinct  alkaloids  or  mixtures  of  alkaloids.  Wright  and  Luff, 
and  also  Couerbe,  applied  it  to  an  alkaloid  that  is  also  known 
as  I'cratridinc;  Merck,  Bosetti,  Ahrens,  and  others,  to  an  alkaloid 
known  also  as  ccvadine;  the  United  States  Pharmacopoeia 
applies  it  to  a  variable  mixture  of  several  alkaloids  which  are 
yielded  by  an  entirely  different  plant.  Which  of  these  is  em- 
ployed in  pharmacologic  investigations  has  not  always  been 
stated  in  the  reports. 

Veratrum  viride  contains  cevadine  as  its  chief  constituent. 
It  also  contains  protoveratrine,  veratridine,  jervine,  rubijervine 


VERATRUM  237 

(acrid) ,  pseudo-jervine  (inactive) ,  and  some  irritant  resin.     Wood 
says  that  it  contains  only  traces  of  protoveratrine. 

Veratrum  album,  an  unofficial  species  that  grows  in  Europe, 
owes  its  essential  activity  to  protoveratrine.  It  contains  also 
jervine,  rubijervine,  and  acrid  resin,  but  not  cevadine. 

Veratrine,  U.  S.  P.,  contains  cevadine  as  its  essential  con- 
stituent, and  also  cevadilline,  sabadine,  sabadinine,  and  vera- 
tridine.  It  is  obtained  from  the  seeds  of  Asagr&a  qfficinalis,  or 
sabadilla  (Fam.  Liliaced). 

Preparations  and  Doses. — Veratrum,  2  grains  (0.13  gin.). 
Fluidextract,  2  minims  (0.13  c.c.).  Tincture,  10  per  cent.,  20 
minims  (1.3  c.c.).  Collins  states  that  the  full 
therapeutic  dose  for  adults  is  30  to  75  minims 
(2-5  c.c.)  of  the  tincture,  and  that  if  given  with 
i  to  3  glasses  of  water  it  does  not  irritate  the 
stomach. 

Veratrine,  the  official  mixture   of  alkaloids 

from  sabadilla  seeds,  is  assigned  the  dose  of  A-     Flg-  39.— Normal 

•      (  \  u      ..-u      -nif  •       u    i.  •*          muscle  curve, 

grain  (0.002  gm.)  by  the  Pharmacopoeia,  but  it 

is  a  drug  of  too  great  power  and  uncertainty  for  internal  use. 
Pharmacologic  Action. — Locally,  all  veratrum  preparations 
are  very  irritant,  both  because  of  their  alkaloids  and  because  of 
the  presence  of  acrid  resin.  If  the  dust  is  inhaled,  it  causes  vio- 
lent sneezing  and  coughing.  If  a  preparation  is  swallowed  in- 
sufficiently diluted,  it  may  cause  vomiting;  or  if  not  vomited, 
diarrhea  and  colicky  pains. 

Cevadine  (frequently  called  veratrine)  is  more  irritant  locally 
than  aconitine,  but  acts  like  aconitine  on  the  vagus  center. 
Pilcher  and  Sollmann  state  that  there  is  no 
direct  action  on  the  vasomotor  centers.     It  is 
also  a  general  muscular  stimulant,  inducing 
increased  irritability  and  increased  power  in 
all  kinds  of  muscle.     In  experiments  with  a 
frog's  gastrocnemius,   for  example,  it  causes 
Fig-  3I-  _  Veratrine     increased  quickness  and  length  of  contraction, 
muscle  curve.          increased   lifting  and   sustaining  power,   and 
lessened  fatigue.     That  this  is  a  pure  muscu- 
lar   stimulation    is    shown  by    its    taking  place   after  the  end- 
plates  are  paralyzed  by  curare.     But  there  is  a  peculiar  phe- 
nomenon  in   the   muscular    relaxation,   for    this    is    found    to 
take  place  very  slowly  indeed,  so  that  quite  an  interval  elapses 
before   the   muscle  is   ready   to   contract   again.     It  might  be 
thought  that  this  tardy  relaxation  is  due  to  a  loss  of  muscle 
elasticity,  but  this  is  not  the  case,  and  that  the  muscle  is  in 
an  active,  though  diminishing,  state  of  contraction  is  shown  by  its 


238  PHARMACOLOGY   AND   THERAPEUTICS 

ability  to  sustain  weight  during  the  relaxation,  and  by  the  con- 
tinuous production  of  heat,  which  indicates  that  work  is  being 
done.  This  reaction  of  muscle,  which  occurs  also  from  other 
drugs,  is  known  in  pharmacology  as  the  "veratrine  action." 
From  therapeutic  doses  this  effect  on  relaxation  is  not  observed, 
while  there  is  distinct  stimulation  of  striated  muscle.  Hence,  it 
is  evident  that  cevadine  (veratrine)  is  a  muscular  stimulant,  and 
not,  as  at  one  time  taught,  a  muscular  depressant. 

Protoveratrine  resembles  aconitine  in  its  effects  upon  the 
circulation,  though  it  is  nearly  twice  as  toxic  (o.n  mg.  per  kilo  in 
rabbit,  Eden).  It  is  not  so  irritant  locally  as  cevadine,  and  the 
irritation  may  be  followed  by  local  anesthesia.  It  stimulates 
strongly  the  vagus  center,  and  in  large  doses  the  vasoconstrictor 
center  and  the  cardiac  muscle,  the  stimulation  being  followed  by 
depression  of  these  structures  in  the  same  order.  Like  cevadine, 
it  is  a  stimulant  of  muscle,  increasing  its  irritability  and  the 
strength  and  completeness  of  its  contraction;  but  the  relaxation 
is  prompt  and  not  prolonged,  as  with  cevadine,  and  muscle 
fatigue  sets  in  early. 

Circulation. — After  therapeutic  doses  of  any  of  the  prepara- 
tions there  is  pure  slowing  of  the  heart  by  vagus  stimulation  and 
a  lowering  of  arterial  pressure,  with  perhaps  slight  stimulation 
of  muscle.  After  toxic  doses  there  are:  excessive  slowing,  with 
perhaps  irregularity  or  intermittence  from  vagus  stimulation, 
then  quickening  and  strengthening  of  the  heart  from  vagus 
paralysis,  with  vasoconstriction  and  raised  arterial  pressure, 
then  cardiac  exhaustion  and  collapse.  Death  takes  place  with 
asphyxia  from  paralysis  of  the  respiratory  center,  which  is  con- 
tributed to  by  the  heart  failure. 

Toxicology. — The  poisoning  and  its  treatment  are  those  of 
aconite,  but  veratrum  is  much  more  likely  to  be  expelled  by 
vomiting,  owing  to  its  very  irritant  local  action  in  the  stomach. 

Therapeutics. —  Veratrine  has  been  used  externally  as  a 
slowly  acting  anesthetic  in  muscular  pains  and  neuralgia,  espe- 
cially in  facial  neuralgia.  But  its  primary  irritation  prevents  it 
from  being  a  favorite  preparation;  and  as  it  may  be  absorbed 
through  the  skin,  especially  when  in  the  form  of  the  oleate,  its 
local  use  is  not  without  danger. 

Veratrum  is  used  to  slow  a  rapid  heart,  to  quiet  an  overacting 
one,  and  to  reduce  high  blood-pressure.  In  clinical  cases  Collins 
has  shown  its  pronounced  effect  on  the  rate  of  the  heart  and  on 
both  diustolic  and  systolic  pressures.  Its  chief  employment  has 
been  in  eclampsia,  a  condition  in  which  very  large  doses  of  vera- 
trum have  been  employed,  and  at  times  with  an  astounding  but 
valuable  depression  of  the  arterial  tension.  Starling  and  Hirst, 


NITRITES  239 

independently,  have  made  studies  of  the  arterial  pressure  in 
pregnant  women,  and  both  have  found  that  high  pressure  means 
toxemia.  In  one  of  Hirst's  eclamptic  cases  the  pressure  was 
320  mm.^of  mercury.  The  drug  is  not  an  arterial  dilator,  there- 
fore it  might  well  be  accompanied  by  nitroglycerin;  and  caution 
must  be  employed  not  to  overdo  the  depression.  The  author's 
attention  has  been  called  to  the  occurrence  of  collapse  in  a  number 
of  eclampsia  cases  following  the  administration  of  veratrum  in 
large  doses  for  two  or  three  days. 

ARTERIAL  DILATORS 

The  drugs  most  employed  to  dilate  the  arteries  are  those  of 
the  nitrite  group,  and  to  a  slight  extent  chloral  hydrate  and  potas- 
sium iodide. 

NITRITES 

The  pharmacologic  group  of  nitrites  includes  the  nitrites  of 
amyl,  ethyl,  and  sodium,  and,  in  addition,  certain  drugs  which 
are  not  nitrites,  but  yield  nitrites  by  their  decomposition.  The 
alkali  nitrates  have  no  effect  upon  arterial  pressure,  but  potas- 
sium nitrate  is  a  salt  which  forms  nitrites  when  it  is  burned, 
though  it  does  not  do  so  in  the  body;  and  nitroglycerin,  erythrol 
tetranitrate,  and  mannitol  hexanitrate  are  organic  nitrates  which 
liberate  nitrites  in  the  blood. 

Preparations  and  Doses. — Amyl  nitrite,  amylis  nitris,  C5Hn- 
NO2,  dose,  2-5  minims  (0.13-0.3  c.c.),  is  an  unstable  liquid  with  a 
banana-like  ethereal  odor.  It  is  very  volatile,  and  decomposes 
slowly  when  exposed  to  air  and  light.  For  convenience,  it  is  sold 
in  capsules  or  ampules  of  dark  glass,  containing  two,  three,  four, 
or  five  minims.  The  drug  is  employed  by  inhalation,  the  vapor 
being  liberated  by  breaking  one  of  these  capsules  in  a  handker- 
chief or  piece  of  gauze. 

Sodium  nitrite,  sodii  nitris,  NaNO2,  dose,  i  grain  (0.06  gm.), 
is  a  non-volatile  and  non-explosive  deliquescent  salt,  which  is 
freely  soluble  in  water  (1.4  part).  It  has  an  affinity  for  oxygen, 
and  is  used  in  chemistry  as  a  deoxidizing  agent.  In  the  air  it 
gradually  oxidizes  to  nitrate  and  loses  its  efficiency;  and  because 
of  this,  is  the  least  certain  of  the  group.  When  given  during  the 
digestive  period,  i.  e.,  while  there  is  free  HC1  in  the  stomach,  it 
sets  free  nitrous  acid,  which  is  not  only  irritating  to  the  stomach, 
but  may  be  somewhat  oxidized  and  rendered  inert  before  absorp- 
tion. 

Nitroglycerin,  glyceryl  trinitrate,  trinitrin,  or  glonoin,  C3H5- 
(XO3)3,  is  the  volatile,  highly  explosive  liquid  which  is  used  in 
the  manufacture  of  dynamite.  It  is  decomposed  and  rendered 


240  PHARMACOLOGY  AND  THERAPEUTICS 

non-explosive  by  strong  alkalis.  Its  dose  is  rf0  grain  (0.0006 
gm.) .  Its  only  official  preparation  is  the  spirit  of  glonoin  (spiritus 
glycerylis  nitratis),  an  alcoholic  solution  of  i  per  cent,  by  weight 
of  nitroglycerin,  the  dose  of  which  is  i  minim  (0.06  c.c.),  which 
contains  about  iiu  grain  (0.0005  gm.).  It  is  most  commonly 
employed  in  the  form  of  tablet  triturates  or  hypodermatic 
tablets,  and,  because  of  its  volatility,  these  may  be  of  variable 
strength  and  should  be  kept  in  closed  bottles. 

Erythrol  tetranitrate,  CH2CH.CH2(NO3)4,  is  an  unofficial, 
slightly  volatile  solid,  which  is  insoluble  in  water  and  is  highly 
explosive.  A  druggist  is  reported  to  have  had  his  hand  blown 
off  on  rubbing  it  in  a  mortar.  The  dose  is  i  grain  (0.06  gm.), 
in  tablets,  which  keep  best  when  coated.  It  is  rather  expensive. 

Spirit  of  nitrons  ether,  sweet  spirit  of  niter,  is  an  alcoholic 
solution  of  4  per  cent,  by  weight  of  ethyl  nitrite.  Its  dose  is 
30  minims  (2  c.c.),  well  diluted  with  water.  It  is  too  mild  a 
preparation  to  use  as  a  general  arterial  dilator,  and  it  is  employed 
chiefly  in  colds  and  slight  fevers  as  a  diuretic.  It  is  possible 
that  in  these  conditions  it  may  be  of  use  in  counteracting  the 
tendency  to  raised  blood-pressure  that  goes  with  fever. 

Potassium  nitrate,  KNO3,  saltpeter,  niter,  is  a  constituent  of 
gunpowder,  but  is  non-explosive.  It  is  soluble  in  3.6  parts  of 
water.  The  solution  is  used  to  saturate  unsized  (filter)  paper  or 
the  leaves  of  stramonium  or  tobacco;  and  these,  when  dry,  are 
burned,  and  the  fumes  inhaled  for  the  relief  of  bronchial  asthma. 
On  burning,  the  nitrate  liberates  nitrites,  which  check  the  asth- 
matic attack  by  inducing  relaxation  of  the  spasmodically  con- 
tracted bronchial  muscles.  The  nitrate  by  itself  or  simply 
mixed  with  other  drugs  does  not  burn  readily.  Some  of  the 
papers  used  in  cigarette-making  are  impregnated  with  niter  to 
make  them  burn  evenly  without  bursting  into  a  flame;  in  this 
case  the  niter  may  incidentally  serve  the  useful  purpose  of 
antagonizing  the  primary  rise  in  blood-pressure  caused  by  nico- 
tine. 

Pharmacology. — Almost  the  sole  use  of  nitrites  in  medicine 
is  to  relax  constricted  arteries  and  constricted  bronchi. 

The  Arteries. — If  a  nitrite  is  added  to  the  liquid  used  in  per- 
fusing an  isolated  viscus  or  a  severed  limb,  the  flow  through  the 
viscus  or  limb  is  greatly  increased,  and  even  doubled  or  trebled. 
It  is  evident,  therefore,  that  the  drug  acts  peripherally  to  dilate 
the  arterioles  to  a  marked  degree.  A '  central  action  is  not 
a  factor  in  the  lowering  of  the  pressure,  i.  e.,  there  is  neither 
depression  of  the  vasoconstrictor  center  nor  stimulation  of  the 
vasodilator  center,  and  Pilcher  and  Sollmann  even  find  a  stimula- 
tion of  the  vasoconstrictor  center,  probably  secondary  to  the 


Aur. 


Yen. 


B.  P. 


Fig.  32. — Nitroglycerin,  0.3  c.c.  of  the  i  per  cent,  spirit  per  kilo,  promptly 
reduced  arterial  pressure  from  105  to  60,  and  this  was  followed  by  an  increase  in 
rate  from  126  to  about  150.  (Tracing  made  by  Dr.  C.  C.  Lieb.) 


NITRITES  241 

lowered  pressure.  How  much  of  the  peripheral  action  is  on  the 
ends  of  the  nerves  and  how  much  on  the  arterial  muscles  has  not 
been  satifactorily  demonstrated;  but  that  the  muscular  action 
is  the  chief  one  is  indicated  by  the  dilatation  of  the  coronary 
arteries,  which  have  no  vasomotor  nerves.  So  the  essential 
action  is  direct  depression  of  the  arterial  muscles.  The  nitrites, 
therefore,  are  true  arterial  dilators.  Cameron  ascertained  that 
on  injecting  T^  grain  (0.6  mg.)  of  nitroglycerin  along  with 
-gVoTT  grain  (0.0075  mg-)  °f  epinephrine,  equivalent  to  £  minim 
(0.008  c.c.)  of  the  solution  of  adrenaline,  there  was  no  essential 
rise  or  fall  in  arterial  pressure,  i.  e.,  these  amounts  practically 
neutralized  each  other  physiologically.  The  action  of  the  nitrites 
is  most  marked  on  the  splanchnic  arteries,  but  it  is  also  pronounced 
in  the  arteries  of  the  limbs,  and  in  the  cerebral  and  coronary 
arteries.  Voegtlin  and  Macht  obtained  prompt  relaxation  in 
the  coronary  arteries,  but  with  strips  of  medium-sized  pulmonary 
arteries  Macht  obtained  constriction.  In  arteriosclerosis  the  fall 
in  arterial  pressure  is  not  so  readily  produced,  and  when  pro- 
duced, may  be  maintained  for  a  longer  time  than  normally. 
Of  the  surface  vessels,  those  of  the  head  and  neck,  the  blushing 
area,  are  especially  dilated. 

The  veins  are  also  somewhat  relaxed,  but  this  has  not  been 
shown  to  have  any  therapeutic  importance. 

The  Heart.—  On  the  isolated  heart  ordinary  doses  have  no 
effect,  whether  the  ends  of  the  vagus  and  accelerator  nerves  are 
paralyzed  or  not.  But  larger  doses  depress  the  vagus,  and  there- 
fore tend  to  increase  the  tone  and  contractility  of  the  heart. 

With  the  fall  in  arterial  pressure  from  an  ordinary  dose  the 
heart's  rate  is  accelerated,  and  after  amyl  nitrite  may  increase 
20  or  30  beats  a  minute.  The  increase  is  due  to  vagus  depres- 
sion, for  if  the  vagus  endings  are  first  paralyzed  by  atropine,  the 
nitrite  does  not  cause  any  additional  increase  in  the  rate  of  the 
heart.  The  question  arises,  "Is  the  vagus  depression  due  to 
the  direct  action  of  the  drug  upon  the  center,  or  is  it  the  regular 
reflex  depression  which  accompanies  lowered  arterial  pressure?" 
Sollmann  brings  forward  some  evidence  that  it  is  due  to  direct 
depression  of  the  vagus  center  by  the  drug.  He  finds  that  if  the 
drug  is  allowed  to  act  upon  the  general  circulation,  but  pre- 
vented from  reaching  the  brain,  there  is  no  increase  in  rate, 
though  the  general  arterial  pressure  is  lowered;  and  if  the  drug 
is  confined  to  the  cerebral  circulation,  the  increased  rate  occurs 
without  a  lowering  in  the  general  arterial  pressure;  other  pharma- 
cologists, however,  consider  it  secondary  to  the  fall  in  pressure. 

The  effects  of  nitrites  upon  the  circulation  are,  therefore — 
(i)  Depression  of  the  arterial  muscles,  resulting  in  dilatation  of 
16 


242  PHARMACOLOGY   AND   THERAPEUTICS 

the  arteries;  (2)  increased  rate  of  the  heart's  beat;  (3)  perhaps 
increased  tone  and  strength  of  the  heart. 

With  all  the  stronger  members  of  the  series,  the  arterial  pres- 
sure shows  a  marked  fall,  and  then  gradually  returns  almost 
or  entirely  to  where  it  was  before.  But  the  drugs  differ  in  their 
rapidity  of  action. 

Amyl  nitrite  is  given  by  inhalation.  The  arterial  pressure  in 
normal  animals  falls  to  the  maximum  degree  almost  instantly, 
rises  again  to  the  original  pressure  in  two  to  five  minutes,  and 
shows  complete  restoration  in  from  fifteen  to  twenty  minutes. 
In  human  cases  with  systolic  pressure  above  200  mm.  Hg  the 
author  has  found  that  after  5  minims  of  amyl  nitrite  the  change 
in  pressure  varies  considerably.  It  might  drop  as  much  as  70 
mm.,  to  rise  again  almost  to  the  original  height  in  about  five 
minutes.  But  so  marked  a  fall  in  pressure  is  unusual,  the  change 
being  mostly  between  20  and  40  mm.  In  some  of  these  high- 
pressure  cases  the  response  is  very  little,  and  in  a  few  cases  there  is 
actually  a  rise  in  pressure  of  10  to  20  mm.  The  action  of  amyl 
nitrite  is  too  fleeting  for  use  except  in  emergencies. 

Nitroglycerin  is  given  by  mouth  or  hypodermatically,  and  in 
either  case  is  almost  instantly  absorbed.  The  fall  in  pressure 
begins  in  one-half  to  three  minutes,  reaches  its  maximum  in  five 
to  fifteen  minutes,  and  disappears  in  one-half  to  one  hour.  In 
conditions  of  general  arteriosclerosis  the  effect  sometimes  lasts 
several  hours,  and  sometimes  there  is  no  change  in  pressure  at  all. 

Sodium  nitrite  is  given  by  mouth,  and  is  less  rapidly  absorbed. 
It  has  been  reported  by  G.  A.  Gibson  and  others  as  less  effective 
than  nitroglycerin,  but  recently  several  investigators  (Matthews, 
and  Wallace  and  Ringer,  and  Lawrence)  have  found  it  just  as 
active  as  the  other  preparations,  though  slower  in  its  action.  Its 
effects  come  on  in  five  to  thirty  minutes,  reach  their  maximum 
in  twenty  to  eighty  minutes,  and  are  completely  over  in  one  to 
two  hours.  In  solution  the  nitrite  changes  to  nitrate  on  expo- 
sure to  air,  and  this  may  account  for  the  adverse  clinical  reports. 

Erythrol  tetranitrate  is  administered  by  mouth,  and  is  likely 
to  be  more  slowly  absorbed  and  more  slowly  decomposed  by  the 
blood.  As  a  consequence,  its  effects  are  more  gradual  in  their 
development.  The  drop  in  pressure  begins  in  five  to  thirty 
minutes,  reaches  its  maximum  one-half  hour  to  two  hours  later, 
and  disappears  in  two  to  five  hours. 

Mannitol  hexanitrate  has  an  effect  about  the  same  as  that  of 
erythrol. 

Wallace  and  Ringer  found  that  with  any  member  of  the 
series  the  greater  the  dose,  the  greater  was  the  fall  in  pressure. 
In  one  of  their  cases  ^0  grain  of  nitroglycerin  reduced  the  pres- 


NITRITES  243 

sure  from  210  to  60  mm.  Hg  in  ten  minutes,  the  pressure  rebound- 
ing to  168  mm.  in  four  minutes,  and  reaching  its  original  figure 
in  fifty  minutes.  In  another  patient  sodium  nitrite  caused 
the  pressure  to  fall  from  210  to  100  mm.  In  cases  with  high 
arterial  pressure  the'  author  has  never  secured  such  striking 
results,  even  from  the  administration  of  -5*5  grain  of  nitro- 
glycerin  hypodermatically  every  two  minutes  for  five  doses. 

Blood. — After  enormous  doses  the  hemoglobin  is  reduced  and 
its  power  of  liberating  oxygen  lessened  by  the  formation  of 
methemoglobin  and  nitric  oxide  hemoglobin.  But  in  the  thera- 
peutic use  of  the  drug  this  reduction  is  never  enough  to  produce 
ill  effects,  and  even  after  very  large  therapeutic  amounts  no 
methemoglobin  has  been  present  in  the  blood. 

Respiratory  System. — The  nitrites  stimulate  the  respiratory 
center,  so  that  breathing  is  deeper  and  more  rapid.  This  may 
be  because  of  increased  supply  of  carbon  dioxide  from  improved 
medullary  circulation.  From  very  large  doses  there  is  later  a 
depression  of  the  center  and  asphyxia.  In  bronchial  asthma 
nitrites  may  be  effective  in  overcoming  the  spasm  of  the  bronchial 
muscles.  This  is  a  direct  muscular  effect,  and  is  not  antagonistic 
to  the  action  of  epinephrine  in  the  same  condition.  (When  amyl 
nitrite  is  inhaled,  it  may  cause  a  momentary  reflex  stoppage  of 
respiration  from  irritation  of  the  respiratory  passages,  but  this  is 
of  no  significance,  for  the  respiration  goes  on  again  immediately.) 

Cerebrum. — There  is  no  direct  action  on  the  brain  structures. 
The  cerebral  arteries  are  dilated  along  with  all  others,  and 
either  because  of  this  or  of  the  general  fall  in  pressure,  there  may 
be,  after  amyl  nitrite  or  nitroglycerin,  dizziness,  blurring  of 
the  sight,  and  a  momentary  faintness.  Frequently  after  nitro- 
glycerin and  erythrol  tetranitrate  there  is  such  severe  occipital 
headache  that  the  administration  requires  to  be  stopped.  In 
animal  experiments  convulsions  of  cerebral  origin  have  been 
noted  after  large  doses. 

Medulla. — The  respiratory  center  is  somewhat  stimulated. 
The  vagus  center  is  depressed. 

Eye. — Besides  the  temporary  blurring  of  the  sight,  which  is 
due,  perhaps,  to  dilatation  of  the  retinal  arteries,  dark  objects 
may  appear  to  be  surrounded  by  yellow  and  blue  rings. 

Muscle. — Other  muscles  are  not  so  much  depressed  as  those 
of  the  arteries,  yet  in  bronchial  asthma  the  bronchial  muscles 
may  be  enough  depressed  to  lessen  their  spasmodic  contraction 
and  bring  relief.  This  is  commonly  brought  about  by  the  inhala- 
tion of  the  fumes  from  burning  potassium  nitrate.  Occasionally 
spasm  of  the  ureter  or  common  bile-duct  from  the  presence  of  a 
stone  has  been  overcome  by  nitroglycerin. 


244  PHARMACOLOGY   AND   THERAPEUTICS 

Temperature  may  be  lowered,  owing  to  dilatation  of  the 
cutaneous  vessels  and  the  accompanying  sweating,  but  this  is 
not  a  marked  effect. 

Excretion  is  by  the  kidneys,  chiefly  as  nitrates.  After  large 
amounts  of  nitroglycerin  this  may  appear  unchanged.  The  dose 
is  too  small  to  have  any  appreciable  effect  upon  the  amount  of 
the  nitrogen  elements  of  the  urine. 

Kidneys. — With  the  nitrites,  any  change  in  the  amount  of 
urinary  excretion  depends  upon  the  relation  between  the  fall 
in  general  blood-pressure  and  the  dilatation  of  the  renal  arteries. 
The  effect  is  not  constant,  though  in  some  cases  marked  diuresis 
will  follow  nitrite  administration. 

Toxicology. — It  is  a  common  thing  for  therapeutic  doses  of 
amyl  nitrite  or  nitroglycerin  to  be  followed  immediately  by  a 
pounding  heart,  flushing  of  the  face  and  neck,  and  throbbing 
and  fulness  in  the  head,  with  a  feeling  "as  if  the  top  of  the  head 
were  coming  off."  In  addition,  there  may  be  confusion  of  ideas, 
blurring  of  the  sight,  dizziness,  and  a  feeling  of  faintness.  Such 
effects  are  distressing  to  the  patient,  but  are  quickly  recovered 
from.  Except  for  the  flushing  of  the  face,  they  are  not  nearly  so 
striking  when  the  patient  is  lying  down,  and  would  seem  to  be 
due  to  low  cerebral  blood-pressure.  Occasionally  large  doses 
produce  cyanosis  and  collapse.  A  student  in  our  laboratory 
fainted  after  the  inhalation  of  5  minims  of  amyl  nitrite.  He  was 
in  the  upright  position  when  the  drug  was  administered,  and  his 
systolic  pressure  had  been  recorded  as  only  88  mm.  On  the 
other  hand,  D.  D.  Stewart  gave  a  man  50  minims  of  a  10  per 
cent,  solution  of  nitroglycerin  four  times  a  day — i.  e.,  20  grains 
of  nitroglycerin  in  a  day — without  untoward  effects.  Very 
large  doses  have  been  given  to  animals  without  causing  death 
and  there  are  no  reported  cases  of  death  in  man.  Any  nitrite 
may  be  followed  by  a  headache,  but  persistent  severe  headache 
is  most  common  with  nitroglycerin  or  erythrol  tetranitrate 

Therapeutics. — i.  To  lower  abnormally  high  general  arterial 
pressure,  as  in  chronic  nephritis,  the  dose  being  administered  from 
three  times  a  day  to  every  hour.  It  is  especially  prone  to  fail  in 
cases  with  edema.  But  it  must  be  noted  that  in  cases  with 
long-continued  high  arterial  pressure  it  is  not  considered  wise  to 
bring  the  arterial  pressure  down  to  normal,  for  the  high  pres- 
sure may  really  be  a  response  to  a  need  of  one  or  other  organ 
for  a  greater  supply  of  blood.  In  nephritis,  for  example,  the 
lowering  of  a  chronically  high  pressure  may  result  in  suppression 
of  urine.  On  account  of  the  ephemeral  action  of  the  drug,  com- 
parative daily  blood-pressure  tests  should  follow  the  doses  at 
a  fixed  interval  of  time. 


TO  DECREASE  THE  VOLUME  OF  THE  BLOOD        245 

2.  To  lessen  peripheral  resistance  in  some  cases  of  weak  heart, 
as  in  aortic  insufficiency. 

3.  To  dilate  the  peripheral  arteries  in  local  -uasomotor  spasm, 
as  in  Raynaud's  disease  and  erythromelalgia. 

4.  To  relax  the  coronary  arteries  in  angina  pectoris.     The 
drug  may  be  indicated  even  if  the  general  blood-pressure  is  not 
high;  but  it  is  said  to  be  contraindicated  in  marked  coronary 
sclerosis  with  myocarditis. 

5.  To  relax  the  bronchial  muscles  in  asthma,  especially  by 
burning  niter. 

6.  As  a  diuretic  and  diaphoretic  in  colds  and  mild  fevers — the 
spirit  of  nitrous  ether,  the  alcohol  of  the  spirit  being  probably 
of  as  much  value  as  the  ethyl  nitrite. 

7.  Amyl  nitrite  has  also  been  employed  to  overcome  chloroform 
collapse.     This  is  on  the  theory  that  it  lessens  peripheral  resist- 
ance and  spares  the  exceedingly  weak  heart.     The  author  has 
restored  mice  by  amyl  nitrite  when  they  were  apparently  almost 
dead  from  chloroform.     According  to  Miihlberg  and  Kramer, 
it  is  effective  in  preventing  the  stoppage  of  the  heart  in  the  first 
or  second  stages  of  ether  or  chloroform  anesthetization.     Yet 
some  experiments  with  chloroform  containing   2  per  cent,   of 
amyl  nitrite  have  shown  this  mixture  to  be  more  toxic  than 
chloroform  alone,  so  the  subject  needs  investigation. 

Administration. — For  immediate  and  intense  effect,  amyl 
nitrite  by  inhalation.  For  general  arterial  dilatation,  nitrogly- 
cerin,  which  acts  almost  as  promptly  by  mouth  as  when  given 
hypodermatically,  or  sodium  nitrite  or  erythrol  tetranitrate. 
For  bronchial  relaxation,  inhalation  of  amyl  nitrite,  or  the  fumes 
of  burning  potassium  nitrate,  or  nitroglycerin  by  mouth  or  hypo- 
dermatically. "Asthma  powders"  usually  contain  potassium 
nitrate  with  stramonium,  lobelia,  tobacco,  or  cubebs. 

There  are  two  other  arterial  dilators  in  common  use,  viz., 
potassium  iodide  and  chloral  hydrate.  They  do  not  show  any 
dilator  effect  in  normal  animals,  but  at  times  seem  to  have 
decided  effects  when  there  is  an  abnormally  high  blood-pressure. 
So  far  experiments  with  animals  have  not  taught  us  their  exact 
modus  operandi.  We  speak  of  these  drugs  again. 

MEASURES  FOR  DECREASING  THE  VOLUME  OF  THE  BLOOD 

Blood-letting,  venesection,  or  phlebotomy  is  the  process  of 
removing  blood  from  a  vein,  usually  the  median  cephalic  or 
median  basilic.  To  increase  the  venous  flow  when  necessary,  a 
light  tourniquet  may  be  placed  about  the  upper  arm,  and  the 
forearm  gently  massaged  upward,  or  the  patient  made  to  open 


246  PHARMACOLOGY   AND   THERAPEUTICS 

and  close  the  hand.  A  hollow  vein  needle  is  inserted  into  the 
vein  and  4  to  20  ounces  (120  to  600  c.c.)  allowed  to  flow.  In 
lieu  of  a  needle  the  vein  may  be  cut  down  upon,  tied  off,  and 
snipped  with  scissors. 

Action. — It  has  the  effect  of  lessening  the  systemic  venous 
congestion  and  the  plethora  which  exists  in  a  stagnant  circulation. 
In  conditions  of  circulatory  stagnation  Bolton  and  Starling  found 
that  in  all  phases  of  respiration  there  is  probably  slight  positive 
pressure  in  the  big  veins  near  the  heart  instead  of  the  normal 
alternating  positive  and  negative  pressure,  and  that  this  was  a 
definite  obstruction  to  the  emptying  of  the  lymph  into  the  venous 
system.  They  consider  that  venesection  serves  to  relieve  the 
distention  at  the  venous  end  of  the  heart  and  so  enables  the  heart 
to  beat  more  effectively.  Lazarus-Barlow  noted  a  rise  in  the 
specific  gravity  of  the  tissues  after  bleeding,  that  is,  tissue  fluid 
had  been  removed.  Burton-Opitz  has  shown  that  venesection 
regularly  results  in  a  lowered  viscosity  of  the  blood,  and  Starling 
has  pointed  out  that  by  venesection  not  only  is  diffusible  fluid 
removed  from  the  plasma,  but  also  proteins  in  large  quantity,  and 
that  the  blood  volume  is  quickly  restored  by  absorption  of  iso- 
tonic  tissue  fluid,  so  that  it  becomes  more  watery.  Hill  thought 
that  this  might  result  in  the  mobilization  of  the  opsonins  and 
bactericidal  substances  of  the  tissue  lymph.  Lawrence  believes 
that  repeated  blood-letting  when  indicated  does  not  have  any 
ill  effects  on  the  composition  of  the  blood,  and  Hamburger  demon- 
strated that  the  freezing-point  of  the  blood  remains  unaltered. 

Miller  and  Mathews  in  experimental  edema  of  the  lungs  found 
that  before  any  effect  could  be  seen  on  the  pressure  in  the  pulmon- 
ary artery  it  was  necessary  to  withdraw  a  sufficient  amount  of 
blood  to  lower  the  general  blood-pressure  to  a  dangerous  degree. 
The  pressure  in  the  pulmonary  artery,  however,  is  not  the  crite- 
rion of  the  value  of  any  procedure  in  pulmonary  edema,  as  this 
pressure  is  dependent  on  the  relation  of  the  right  ventricular  out- 
put to  the  caliber  of  the  pulmonary  arterioles.  The  pulmonary 
arterioles,  though  weak  in  muscle,  are  the  gates  which  regulate 
capillary  inflow  and  may  be  looked  upon  as  protectors  of  the 
capillaries. 

Rolla  calls  attention  to  the  lessening  of  the  alkalinity  of  the 
blood  following  venesection,  and  advises  that  when  there  is  a 
tendency  to  acidosis  it  be  accompanied  by  the  administration  of 
alkali. 

Therapeutics. — i.  In  conditions  of  high  venous  pressure,  as 
in  uremia  or  tricuspid  regurgitation  or  tricuspid  stenosis. 

2.  In  conditions  of  venous  accumulation  due  to  a  stagnant 
circulation. 


TO   DECREASE    THE    VOLUME    OF   THE    BLOOD  247 

3.  In  conditions  with  very  high  arterial  pressure,  as  in  uremia 
and  eclampsia.  In  the  author's  clinical  experience  a  marked  and 
prolonged  fall  in  pressure  has  usually  followed  venesection. 

4.  In  acute  pulmonary  edema. 

5.  To  remove  poison — in  uremia,  in  eclampsia,  and  in  carbon 
monoxide  (illuminating  gas)  poisoning.     Its  value  in  removing 
poisons  is  problematic,  for  in  experiments  with  artificially  intro- 
duced toxins  Levin  met  with  negative  results  by  this  method. 

Blood-letting  for  the  removal  of  marked  local  congestion  is 
done  by  the  wet-cup  or  the  leech.  It  has  no  effect  on  general 
blood-pressure. 

Wet-cupping  is  a  process  by  which  blood  is  drawn  from  the 
part  by  suction  through  one  or  more  openings  in  the  skin.  These 
are  made  by  a  scalpel  or  by  a  special  scarificator  which  makes  6 
or  12  cuts  in  two  parallel  rows  {  {  j  j  {  {  .  The  suction  is 
created  in  a  cupping-glass  or  small  tumbler  by  burning  cotton  in  it 
or  swabbing  it  inside  with  burning  alcohol  on  a  cotton  swab.  The 
mouth  of  the  glass  is  quickly  applied  to  the  skin,  and  as  the  heated 
air  cools,  it  creates  suction,  which  results  in  the  withdrawal  of 
serum  or  blood.  Cupping-glasses  may  also  be  had  with  rubber 
ball  or  syringe  attachment  for  creating  suction. 

Wet-cupping  is  but  little  used  today,  though  the  scars  are 
often  seen  in  older  patients.  Its  chief  uses  are — (a)  to  relieve 
edema  of  the  lungs,  the  cups  being  placed  on  the  chest  wall;  (6) 
to  overcome  suppression  of  urine,  the  cups  being  placed  over  the 
kidney  region. 

Dry-cupping — i.  e.,  cupping  without  an  incision  in  the  skin — 
produces  a  local  edema  or  congestion.  It  has  been  referred  to 
with  the  counterirritants. 

The  leech  (hirudo)  is  an  annelid  worm  with  a  sucker  at  each 
end  of  its  body.  At  its  mouth  end  there  are  three  teeth  ar- 
ranged in  a  triradiate  manner,  so  that  its  bite  consists  of  three 
short  deep  gashes  radiating  from  a  common  center.  To  insure 
that  the  bite  shall  be  at  the  desired  spot,  the  leech  is  placed  inside 
a  glass  tube  or  over  a  hole  in  a  piece  of  paper,  the  mouth  of  the 
tube  or  the  hole  in  the  paper  being  placed  over  the  spot  to  be 
bitten.  If  the  leech  does  not  take  hold,  the  skin  may  be  pricked 
or  a  drop  of  blood  or  milk  placed  upon  it,  or  the  leech  may  be  put 
in  very  cold  water  for  a  minute  or  two  to  arouse  it. 

The  effect  of  the  leech  is  that  of  wet-cupping,  more  or  less 
blood  being  extracted.  As  the  mouth  of  the  leech  secretes  a 
substance  (hirudin)  which  prevents  the  coagulation  of  the  blood, 
the  bleeding  may  continue  for  a  long  time  after  the  animal  is 
removed.  Indeed,  it  may  be  necessary  to  employ  something  to 
stop  the  bleeding,  c.  g.,  adrenaline.  The  leech  may  be  removed 


248  PHARMACOLOGY  AND  THERAPEUTICS 

easily  by  squeezing  its  head  or  by  placing  salt  upon  it.  The 
Swedish  leeches  are  considered  the  best,  as  they  extract  about 
half  an  ounce  of  blood,  while  the  American  leeches  extract  only 
i  or  2  drams. 

There  are  decided  disadvantages  in  the  use  of  leeches,  viz.: 

1.  They  may  not  be  clean;  in  any  case,  they  cannot  be  aseptic. 

2.  They  may  wander  and  get  into  one  of  the  body  orifices — e,  g., 
the  ear,  nose,  vagina,  etc.     3.  They  remove  an  uncertain  quantity 
of  blood. 

On  these  accounts  the  artificial  leech  is  sometimes  employed. 
It  consists  of  a  syringe  with  a  cup-like  nozzle  and  a  graduated 
barrel  with  which  slow  suction  is  made  over  a  cut  in  the  skin. 
It  is  merely  a  process  of  wet-cupping  with  a  graduated  syringe. 

Hirudin  is  employed  in  laboratory  work  to  prevent  coagula- 
tion of  the  blood,  the  small  amount  of  0.02  gm.  (\  grain)  being 
sufficient  to  keep  1000  c.c.  of  blood  fluid  for  a  considerable  time. 
It  does  not  alter  the  viscosity  of  the  blood,  but  if  used  in  too 
large  quantities,  may  cause  agglutination  and  sedimentation  of 
the  corpuscles  (Bence).  Satterlee  and  Hooker  have  employed 
it  as  an  anti-coagulant  in  blood  transfusion,  using  30  minims 
(2  c.c.)  of  a  i  :  500  solution  in  saline  to  wet  the  inside  of  a  220  c.c. 
receptacle.  This  prevents  coagulation  for  twenty  minutes. 

SHOCK  AND  COLLAPSE 

Following  severe  trauma  or  a  surgical  operation,  there  de- 
velops at  times  a  condition  of  pronounced  muscular  relaxation, 
with  rapid,  weak  heart,  low  blood-pressure,  and  depressed  respira- 
tion. There  is  a  similar  state  into  which  a  patient  may  pass  as 
the  result  of  severe  disease  or  loss  of  blood.  But  whether  the 
effects  when  produced  by  a  severe  infection  acting  steadily  for 
clays  are  the  same  as  those  from  trauma,  or  are  produced  in  the 
same  manner,  are  questions  not  yet  decided.  And,  further, 
there  is  not  by  any  means  an  agreement  as  to  just  what  does 
happen  in  a  patient  to  bring  him  into  the  state  described,  which 
is  known  as  shock  or  collapse.  There  is  a  tendency  on  the  part 
of  many  writers  to  use  the  term  "collapse"  when  the  prostra- 
tion results  from  toxic  causes,  as  diseases  or  drugs,  or  from  loss 
of  blood,  and  to  confine  the  term  "shock"  to  the  condition 
developed  after  trauma,  either  accidental  or  operative.  But 
the  line  of  differentiation  between  the  two  cannot  be  satisfactorily 
drawn  at  the  present  time.  It  would  seem  to  be  established, 
however,  that  the  central  nervous  system  is  involved,  and  it  may 
be  that  shock  is  due  to  an  overwhelming  inflow  of  powerful 
afferent  impulses,  as  from  the  cut  nerves  of  a  severed  leg. 

In  abdominal  operations  Crile  makes  a  block  between  the 
operative  field  and  the  brain  by  an  infiltration  of  the  skin  and 


SHOCK  AND   COLLAPSE  249 

subcutaneous  tissues  with  j  per  cent,  novocaine,  and  of  the 
peritoneum  with  ^  per  cent,  quinine  and  urea  hydrochloride. 
He  also  lessens  the  perceptive  faculties  by  a  preliminary  injection 
one  hour  before  of  morphine  and  scopolamine.  He  terms  the 
whole  process  anoci-association. 

].  M.  Wainwright's  experiments  (1906)  as  to  the  value  of 
spinal  analgesia  in  shock  from  traumatism  to  the  lower  extremities 
lend  support  to  this  theory.  After  artificial  traumatism,  de- 
signed to  imitate  that  of  a  railway  accident,  he  used  cocaine 
and  stovaine  to  block  the  afferent  impulses.  Two  series  of  his 
experiments  are  of  interest,  viz. : 

1.  Dogs  completely  anesthetized  with  ether  had  their  hind 
limbs  kept  immersed  in  boiling  water.     Some  were  given  spinal 
anesthesia,  some  not.     Those  without  the  preliminary  spinal 
anesthesia  showed  a  short  rise  in  arterial  pressure  for  five  to  ten 
minutes,  then  a  rapid  fall  in  pressure,  and  death  in  twenty-five 
minutes  (average).     In  the  dogs  with  spinal  anesthesia  there  was 
no  change  in  the  arterial  pressure  for  one  hour,  then  a  gradual 
fall  until  death,  presumably  as  the  cocaine  effect  was  wearing  off. 

2.  Dogs  were  completely  anesthetized  with  ether,  and  then 
had  their  hind  legs  crushed  to  a  pulp  by  repeated  blows  of  the 
blunt  side  of  an  ax.     After  twenty  minutes,  given  for  shock  to 
develop,  both  hind  legs  were  amputated  at  the  knee.     A  pre- 
liminary ligation  of  the  femoral  arteries  was  done  to  exclude  the 
effects  of  hemorrhage.     In  all  the  dogs  without  spinal  analgesia 
there  \vas  marked  shock,  and  2  out  of  7  dogs  died  during  or  imme- 
diately after  the  amputation.     The  dogs  which  had  a  spinal 
injection  before  the  amputation  were  all  in  good  condition  after 
the  amputation,  and  remained  so  until  the  cocaine  effect  had 
worn  off. 

Porter  states  that  the  vasoconstrictor  center  is  not  exhausted 
in  shock,  as  it  responds  in  the  usual  way  to  stimuli  through  sen- 
sory nerves.  But  in  well-developed  shock  the  center  is  evidently 
not  easily  influenced,  or  else  the  usual  pressor  influences  are 
changed  to  depressor.  (See  Strychnine.)  And  it  has  been 
suggested  that  in  shock  the  constrictor  synapses  are  easily 
paralyzed,  so  that  the  usual  vasoconstrictor  stimuli  become 
vasodilator.  No  matter  what  the  underlying  factors  involved, 
Hill  figures  that  the  condition  of  shock  or  collapse  is  associated 
with  cessation  of  the  reflexes  which  maintain  the  body  in  a  state 
of  vascular  tone  and  muscular  activity. 

Respiratory  paralysis  must  be  considered  with  collapse.  It 
may  be  due  to  direct  or  reflex  depression  of  the  center,  or  to  the 
failure  of  the  circulation  to  bring  the  center  sufficient  CO2  for 
its  stimulation.  The  symptoms  are  those  of  asphyxia,  resulting 
in  death  unless  artificial  respiration  is  maintained.  If  the  heart 


250  PHARMACOLOGY   AND   THERAPEUTICS 

action  remains  good,  artificial  respiration  may  often  be  continued 
until  the  center  regains  its  activity. 

The  Symptoms  and  Treatment  of  Collapse  and  Shock.— 
Whatever  the  cause  or  the  condition,  therapeutically  there  are 
about  three  distinct  degrees: 

i.  Mild  and  transitory  collapse  is  the  result  of  a  momentary 
suspension  of  the  cerebral  circulation,  as  a  reflex  effect  from 
sudden  emotional  or  psychic  influences,  or  from  a  drug  like  amyl 
nitrite  or  nitroglycerin,  or  from  momentary  ventricular  stoppage, 
as  in  heart-block.  It  is  probably  due  to  anemia  of  the  brain, 
caused  by  the  dilatation  of  the  splanchnic  arterioles,  and  this 
dilatation  is  in  turn  the  result  of  a  failure  of  the  normal  sensory 
impulses  to  have  their  usual  effect  upon  the  vasoconstrictor 
center.  The  symptoms  are  dizziness  and  faintness,  or  fainting. 
Treatment  is  directed  toward  favoring  the  blood-supply  of  the 
medulla.  If  the  patient  feels  faint,  he  may  sit  with  head  down 
between  the  legs  or  may  lie  down;  if  he  has  fainted,  he  should  be 
laid  with  head  lower  than  feet.  Ammonia  smelling-salts,  or  any 
rapidly  acting  strong  carminative,  such  as  aromatic  spirit  of 
ammonia  or  (hot)  whisky,  will  hasten  the  recovery. 

2.  A   moderate  degree  of  collapse  from  poisoning  manifests 
itself  by  the  gradual  onset  of  nausea,  and  perhaps  vomiting, 
diarrhea,    and    abdominal    weakness,    with    profuse    sweating, 
clammy  skin,  and  general  muscular  weakness  and  prostration 
(a  condition  experienced  by  many  embryo  smokers  after  their 
first  cigar). 

3.  Severe  collapse  may  be  gradual  in  its  onset  or  sudden.     It 
may  or  may  not  be  accompanied  by  unconsciousness.     The  face 
is  anxious,  or  if  the  patient  is  unconscious,  may  be  expressionless 
—mask-like.     The  skin  is  cold  and  clammy  and  bathed  in  per- 
spiration.    It  is  usually  cyanotic,  but  is  pale  if  the  collapse  is 
due  to  hemorrhage  or  chloroform.     The  breathing  is  labored  and 
inefficient,  and  may  become  slow  and  shallow,  or  of  the  Cheyne- 
Stokes  type.     The  pulse  is  rapid  and  feeble,  perhaps  almost 
imperceptible.     The  temperature  falls,  and  may  reach  as  much  as 
three  or  four  degrees  below  normal.     The  mind  becomes  dulled 
or  there  is  unconsciousness.     There  is  great  muscular  we'akness 
with  prostration,  and  there  may  be  vomiting  and  convulsions. 

Treatment. — Prophylactic. — Crile's  anoci-association  would 
seem  to  be  a  successful  prophylactic.  Actual — all  would  seem 
to  agree  with  Pike  and  Coombs  that  in  surgical  shock  some  means 
of  raising  the  systemic  arterial  pressure  is  necessary.  But  the 
more  we  know  of  shock  and  collapse,  the  less  we  pin  our  faith 
to  drugs.  If  we  employ  them,  we  must  not  let  the  stress  of  the 
emergency  lead  us  into  giving  them  in  too  large  doses.  In 
such  an  emergency  we  have  seen  drugs  administered  in  amounts 


SHOCK   AND    COLLAPSE  251 

that  might  have  proved  fatal  to  a  healthy  person;  and  it  seemed 
as  if  the  patient  might  have  died  from  the  drugs  rather  than  from 
the  collapse. 

There  are  two  drugs  that  stand  preeminent  as  of  possible 
value  in  raising  the  arterial  pressure,  viz.,  epinephrine  and 
pituitary.  Their  action  is  peripheral,  therefore  takes  place 
whether  the  vasoconstrictor  center  is  paralyzed  or  not.  They 
may  be  added  to  a  saline  infusion  and  administered  very  slowly 
indeed ;  in  this  way  the  action  may  be  obtained  for  an  hour  or  two. 
But  the  shock  may  supervene  at  the  end  of  this  period. 

Besides  this  there  should  be: 

1.  A  position  to  favor  cerebral  blood-supply,  i.  e.,  with   the 
body  tilted  so  that  the  feet  are  higher  than  the  head.     The  legs 
may  even  be  raised  in  the  air  at  a  right  angle  to  the  body. 

2.  Mechanical   measures  to  raise   blood-pressure — the   limbs 
may  be  bandaged  from  fingers  to  shoulders,  or  Crile's  pneumatic 
jacket  applied,  or  weights  and  tight  binders  placed  over  the 
abdomen.     Meltzer  says  this  last  method  may  send  up  the  blood- 
pressure  and  hold  it. 

j.  Absolute  repose. 

4.  Maintenance  of  body  warmth  by  hot  blankets,  hot  towels, 
hot-water  bottles,  hot  drinks,  hot  enemata,  etc. 

5.  Plenty  of  air,  and,  if  necessary,  artificial  respiration  and 
the  inhalation  of  oxygen.     In  edema  of  lungs,  dry-cupping  and 
artificial  respiration  (Emerson),  especially  by  Meltzer's  intra- 
tracheal  insufflation. 

The  treatment  as  outlined  may  need  to  be  modified  accord- 
ing to  the  cause  of  the  collapse.  For  example,  if  the  cause  is 
hemorrhage,  the  chief  end  of  the  medication  is  to  restore  the 
volume  of  the  blood;  if  the  cause  is  heart  failure,  it  may  be 
desirable  to  avoid  vasoconstriction,  i.  e.,  peripheral  resistance  and 
physical  work ;  and  if  the  heart  failure  is  the  result  of  malnutri- 
tion from  failure  of  the  digestive  organs,  as  in  some  post-opera- 
tive cases,  transfusion  of  blood  may  be  indicated.  For  nutrition, 
an  intravenous  of  glucose  may  be  employed  (see  Glucose). 

When  the  heart  has  ceased  to  beat  it  may  sometimes  be  resus- 
citated by  an  injection  of  epinephrine  or  tincture  of  digitalis  into 
the  ventricle  or  pericardial  sac,  especially  if  this  is  combined  with 
massage  of  the  heart  through  a  thoracic  or  abdominal  opening,  or 
by  simple  compression  of  the  thorax  or  abdomen.  Gunn  and 
Martin  recommend  that  the  compression  be  gradual  and  the 
relaxation  abrupt. 

Further  treatment  may  be : 

/.  Stimulants. — The  administration,  by  stomach  or  rectum, 
of  strong  hot  coffee.  The  hypodermatic  administration  of 
stimulants  to  the  central  nervous  system,  the  respiration,  and 


252 


PHARMACOLOGY   AND   THERAPEUTICS 


the  circulation,  such  as  atropine,  caffeine,  strychnine,  or  strophan- 
thin,  according  to  the  several  indications. 

2.  The  administration  of  carbon  dioxide  by  inhalation.  As 
this  gas  does  not  interfere  with  the  oxygen-carrying  power  of  the 
blood,  it  may  be  administered  with  oxygen.  It  stimulates  the 
respiratory  center  and  tends  to  overcome  Cheyne-Stokes  or 
shallow  breathing.  Henderson  says  that  it  should  not  be  given 
in  a  concentration  above  6  per  cent. 

REMEDIES    WHOSE     CHIEF    ACTION    IS    UPON    THE 
CENTRAL  NERVOUS  SYSTEM 

a.  The  stimulants. 

b.  The  depressants. 

Those  which  stimulate  the  central  nervous  system  are: 
caffeine,  strychnine,  atropine,  and  cocaine. 

CENTRAL  NERVOUS  STIMULANTS 
THE  CAFFEINE  GROUP 

This  includes  the  three  alkaloids,  caffeine,  theobromine,  and 
theophylline,  caffeine  being  chemically  a  trimethyl  xanthine, 
and  the  other  two,  dimethyl  xanthines.  They  are  purin  bodies, 
are  closely  related  to  uric  acid,  and  are  but  feebly  basic,  i.  e., 
have  little  power  to  form  salts. 

There  are  three  classes  of  purins: 

1.  The  oxy purins,   which   include   hypoxanthine,   xanthine, 
and  uric  acid  (trioxypurin  or  oxyxanthine) . 

2.  The  ammo  purins,  which  include  adenin  and  guanin. 

3.  The  methyloxy purins,  which  include  this  caffeine  group. 


N  =  CH 

I     I 

HC     C—  NH 


jj c N 

Purin,  C8H4N4 

HN— CO 
OC     C— NH 


HN—  C—  N 

Xanthine,  C6H4N4O2 

HN—  CO 

OC     C—  NCH3 


CHj—  N—  C—  N 

Theobromine. 


HN—  CO 

I       I 
OC    C—  NH 


HN—  C—  NH 

Uric  acid,  C6H4N4O3 

CHs—N—  CO 

OC    C—  NCH3 


Ha—  N—  C—  N 

Caffeine,  trimethyl 
xanthine. 

Ha—  N—  CO 
OC     C—  NH 


CHs—  N—  C—  N 

Theophylline. 


CAFFEINE  253 

By  these  formulae  the  purin  nature  of  the  drugs  of  this  group 
is  evident,  as  also  their  close  relation  to  uric  acid. 


CAFFEINE 

Trimethylxanthine,  or  caffeine,  is  a  feebly  basic  alkaloidal 
body  usually  prepared  from  damaged  tea-leaves.  It  is  found  in 
plants  growing  in  different  parts  of  the  world,  and  of  no  close 
botanic  relationship ;  and  the  finding  out,  by  the  inhabitants  of 
these  different  countries,  of  the  value  of  their  particular  plant  in 
making  a  stimulating  beverage,  and  of  the  best  way  of  preparing 
the  part  of  the  plant  used,  makes  an  interesting  story. 

In  Arabia  and  Egypt  the  beverage  was  made  from  coffee, 
the  roasted  seeds;  in  western  Africa,  from  kola,  the  dried  seeds; 
in  the  Amazon  region  of  South  America,  from  guarana,  a  brittle 
mass  made  by  pounding  up  the  seeds  to  a  paste  and  drying  by 
heat;  in  China  and  Japan,  from  tea,  the  fermented  leaves;  in 
Paraguay  and  Uruguay,  from  mate  or  Paraguay  tea,  the  dried 
leaves  and  shoots  of  a  species  of  Ilex  or  holly.  The  Appalache 
tea  (Ilex  cassine),  which  grows  from  Virginia  to  the  Gulf  of 
Mexico,  contains  0.12  per  cent,  of  caffeine  and  2.4  per  cent,  of 
tannin  (Blyth,  1909).  Having  no  caffeine  plants,  the  inhabit- 
ants of  Mexico  and  the  West  Indies  made  their  stimulating 
beverage  of  the  fermented  seeds  of  the  chocolate  plant,  which 
contain  the  close  relative,  theobromine.  Mate  contains  about 
1.3  per  cent,  of  the  alkaloid;  tea,  i  to  4  per  cent.;  coffee,  0.6  to 
2  per  cent. ;  kola,  i  to  2  per  cent. ;  and  guarana,  3  to  6  per  cent. 

Preparations  and  Doses. — Caffeine  (caffeina)  is  soluble  in 
46  parts  of  water  and  54  of  alcohol.  Dose,  i  grain  (0.06  gm.). 

Citrated  caffeine  (caffeina  citrata)  is  a  mixture  of  equal  parts 
of  caffeine  and  citric  acid.  On  account  of  the  feebly  alkaloidal 
nature  of  caffeine,  the  citric  acid  is  added  in  excess.  It  is  soluble 
in  25  parts  of  water.  Dose,  2  grains  (o.  13  gm.).  This  is  the 
favorite  preparation. 

Effervescent  citrated  caffeine  (caffeina  citrata  effervescens)  is 
a  granular  salt  which  contains  4  per  cent,  of  citrated  caffeine, 
i.  e.,  2  per  cent,  of  caffeine,  with  citric  and  tartaric  acids  and 
sodium  bicarbonate  to  make  it  effervesce  when  added  to  water. 
Dose,  50  grains  (about  two  teaspoonfuls). 

Guarana  is  assayed  to  contain  not  less  than  4  per  cent,  of 
alkaloid.  It  contains  much  tannic  acid.  It  has  one  official 
preparation,  the  fluidextract,  dose,  30  minims  (2  c.c.). 

Caffeine  sodio-benzoate  and  caffeine  sodio-salicylate  are  double 
salts  which  are  soluble  in  twice  their  weight  of  water,  and  can 
be  used  hypodermatically.  Dose,  2  grains.  (0.13  gm.).  The 


254  PHARMACOLOGY    AND    THERAPEUTICS 

salicylate  contains  about  6  per  cent,  and  the  benzoate  about  50 
per  cent,  of  caffeine.  In  emergencies,  caffeine  is  employed  in 
two  or  three  times  the  amounts  stated. 

Pharmacologic  Action. — Alimentary  Tract. — The  taste  is  bit- 
ter. There  is  no  direct  action  upon  the  tissues,  but  through 
nervous  effects  there  may  be  hyperacidity  and  nausea. 

Absorption  is  fairly  rapid  from  the  stomach  and  intestines. 
Cerebral  stimulation  from  stomach  doses  is  evident  in  from  one- 
half  hour  to  one  and  one-half  hours. 

Nervous  System. — Coffee  and  tea  are  so  much  used  as  bever- 
ages that  their  stimulating  and  nervous  effects  are  well  known  to 
the  laity.  These  effects  are  of  importance  not  only  in  the  me- 
dicinal use  of  the  drug,  but  also  because  of  overindulgence  in 
the  beverages. 

Cerebrum. — After  a  fair  dose  of  caffeine  the  mind  becomes 
more  alert,  the  attention  keener,  and  the  spirits  brighter;  or  a 
state  of  drowsiness  and  inattention  will  be  changed  to  one  of 
wakefulness  and  brightness  and  activity.  In  other  words, 
there  is  a  real  stimulation  of  the  intellectual  functions,  especially 
those  of  reason,  judgment,  will,  and  self-control,  the  highest 
functions  of  the  mind.  At  the  same  time  the  perceptions  are 
more  acute,  the  appreciation  of  pain  is  heightened,  and,  as  shown 
by  the  esthesiometer,  the  sense  of  touch  is  more  discriminating. 
Kraepelin  found  that  the  reception  of  sensory  impulses  and  the 
association  of  ideas  are  facilitated,  but  the  transmission  of 
thought  into  action  is  retarded.  This  is  because  of  the  inter- 
vention of  judgment.  Caffeine  also  stimulates  the  motor  areas 
of  the  brain,  as  indicated  in  a  dog  by  the  greater  motor  response 
to  a  given  electric  stimulus  of  the  exposed  motor  area,  and  as 
shown  in  man  by  increased  activity  of  voluntary  motion.  So 
caffeine  is  a  true  stimulant  of  the  intellectual  and  motor  centers 
of  the  cerebrum.  It  is  directly  antagonistic,  in  its  cerebral 
effects,  to  alcohol.  Doses  of  8  to  15  grains  (0.5  to  i  gm.)  given 
to  students  produce  overexcitability,  agitation,  and  inability  to 
concentrate. 

Hollingworth,  in  his  laboratory  of  psychology  at  Columbia, 
experimented  on  6  assistants  and  16  students  for  a  period  of 
forty  clays.  He  used  capsules  of  citrated  caffeine,  with  capsules 
of  sugar  of  milk  as  controls.  None  of  the  subjects  knew  which  of 
these  was  being  taken.  He  made  76,000  measurements  and  800 
efficiency  curves,  with  and  without  caffeine.  Of  the  citrated 
caffeine,  which  is  of  50  per  cent,  strength,  i  to  4  grains  produced 
slight  nervousness,  not  noticeable  until  several  hours  after  the 
dose.  There  were  increased  speed  and  accuracy  of  movement, 
beginning  in  about. an  hour  and  lasting  about  four  hours.  Six 
grains  produced  marked  unsteadiness. 


CAFFEINE  255 

In  typewriting,  small  doses  increased,  and  doses  above  three 
grains  retarded,  the  speed;  but  the  quality  of  the  work,  even 
with  the  larger  doses,  was  superior  to  that  of  the  same  subjects 
on  control  days.  There  was  no  fatigue  reaction  to  the  extra 
work. 

In  calculations,  there  was  marked  increase  in  ability,  the 
stimulation  beginning  in  about  one  hour  and  lasting  several  hours. 
The  morning  following  the  experiment  showed  without  excep- 
tion a  clear  improvement  over  the  work  of  the  morning  preceding 
the  experiment. 

In  sick  people,  the  condition  of  wakefulness  and  keener  per- 
ception brought  about  by  caffeine  is  usually  highly  undesirable ; 
and  in  habitual  insomnia  one  of  the  first  things  to  look  out  for 
is  that  the  patient  shall  not  take  tea  or  coffee  toward  evening. 

Medulla. — Caffeine  stimulates  strongly  the  respiratory  center, 
and  slightly  the  vasoconstrictor  and  the  vagus  centers. 

Spinal  Cord. — Caffeine  stimulates  the  motor  cells  and  pro- 
motes the  passage  of  impulses  through  the  spinal  cord  in  the  same 
manner  as  strychnine,  but  to  a  much  smaller  degree.  (See 
Strychnine  for  more  detailed  study  of  this  property.)  It  there- 
fore increases  reflex  activity,  and  tends  to  improve  the  "tone" 
of  muscle;  and  in  marked  amounts  may  cause  twitching  of  the 
limb  and  face  muscles.  In  the  laboratory  it  is  often  noticed  that 
an  animal  lightly  anesthetized  with  ether  or  chloroform  will 
become  conscious  and  recover  its  reflexes  if  a  hypodermic  of 
caffeine  is  administered. 

Muscle. — If  the  gastrocnemius  of  a  curarized  frog  is  painted 
with  a  weak  solution  of  caffeine,  or  if  caffeine  is  injected  into  its 
supplying  artery,  the  muscle  will  contract  more  promptly  and  to 
a  smaller  stimulus,  and  will  lift  a  heavier  load,  i.  e.,  its  irritability 
and  its  strength  are  increased  by  the  direct  action  of  the  drug. 
The  total  work  of  the  muscle  before  fatigue  sets  in  is  also  in- 
creased. Such  direct  stimulation  occurs  in  both  striated  and 
cardiac  muscle,  but  not  to  any  great  extent,  if  at  all,  in  smooth 
muscle,  though  the  latter  may  be  improved  in  tone  (Sollmann 
says  that  smooth  muscle  is  stimulated).  From  overdoses  the 
typical  phenomena  of  fatigue  come  on  early,  the  muscle  being 
poisoned.  In  frogs,  large  doses  induce  a  stiffening  of  the  muscle 
like  that  of  rigor  mortis;  in  mammals  this  effect  is  not  seen,  as 
death  takes  place  before  this  stage  is  reached. 

Power  and  Endurance. — Human  experiments  with  the  ergo- 
graph  show  greater  power  and  greater  endurance  of  the  finger 
muscles.  In  comparative  experiments  with  whole  companies  of 
soldiers  on  the  march  under  like  conditions,  Leistenstorfer,  for 
the  German  government,  found  that  when  the  soldiers  were  well 


256  PHARMACOLOGY   AND   THERAPEUTICS 

supplied  with  food,  those  that  were  given  tea  or  coffee  could 
endure  more  prolonged  and  more  severe  marches  than  those  that 
did  not  get  tea  or  coffee.  If  no  food  was  supplied,  fatigue 
appeared  first  in  the  tea-  and  coffee-drinkers.  That  is  to  say, 
tea  and  coffee  increased  the  power  for  continuous  physical  work 
so  long  as  the  supply  of  nutritive  material  was  ample,  but  caused 
early  exhaustion  when  food  was  withheld. 

Caffeine  thus  may  act  to  increase  the  capacity  for  work  in 
several  ways,  viz.:  i.  By  increasing  mental  vigor.  2.  By 
stimulating  the  motor  areas  of  the  brain  and  so  increasing  the 
range  and  control  of  voluntary  acts.  3.  By  increasing  the  motor 
activity  of  the  cord  and  so  improving  the  tone  of  muscle.  4.  By 
directly  stimulating  the  voluntary  muscles  themselves. 

Circulatory  System. — In  the  isolated  heart,  the  beats  under 
caffeine  are  increased  in  frequency  and  are  stronger,  i.  e.,  the 
heart  will  contract  against  a  greater  aortic  pressure.  As  this  is 
the  result  whether  the  vagus  and  accelerator  endings  have  been 
paralyzed  or  not,  it  must  be  due  to  direct  stimulation  of  the 
heart  muscle.  In  the  intact  mammal,  after  a  good-sized  dose, 
the  rate  is  not  much  accelerated  and  may  even  be  slowed,  the 
effect  being  the  resultant  of  a  mild  stimulation  of  the  vagus 
center  and  mild  stimulation  of  the  muscle.  Repeated  medicinal 
doses,  like  the  habitual  drinks  of  tea  and  coffee,  have,  as  a  rule, 
little  if  any  effect  on  the  rate,  the  force,  and  the  output  of  the 
heart. 

In  some  cases  the  heart  muscle  stimulation  is  pronounced 
after  a  single  dose  or  a  cup  or  two  of  coffee ;  and  it  is  possible  that 
in  these  cases  the  increased  heart  action  is  largely  due  to  increased 
flow  through  the  coronary  arteries.  But  sometimes  the  only 
results  in  human  sickness  are  nervousness,  wakefulness,  cardiac 
discomfort,  and  palpitation.  Pilcher  says  that  in  shock  the 
danger  of  cardiac  death  is  increased  by  caffeine. 

Enormous  doses  bring  about  depression  of  the  heart  muscle 
with  slowing,  and  partial  heart-block  has  been  reported  in  ani- 
mals. But  the  author  has  some  clinical  evidence  that  caffeine 
opposes  the  good  action  of  digitalis  in  impairing  conduction  in 
cases  with  auricular  fibrillation;  and  in  cold-blooded  animals, 
C.  C.  Lieb  has  repeatedly,  with  caffeine,  removed  a  heart-block 
that  had  been  produced  with  cocaine.  Barton  has  recently 
reported  the  removal  by  caffeine  of  various  digitalis  arhythmias 
and  heart-block. 

Arteries. — The  vasoconstrictor  center  is  moderately  stimu- 
lated, so  that  the  arteries  may  contract  and  raise  arterial  pres- 
sure. Sollmann  (1910)  says  that  there  is  a  general  peripheral 
vasodilator  action  that  overcomes  the  effect  of  stimulation  of 


Aur. 


Yen. 


B.  P. 


Fig.  33.- — Caffeine,  5  mg.  per  kilo,  resulted  in  increased  contractility  of  auricle 
and  ventricle  (down-stroke),  and  a  rise  in  blood-pressure  from  68  to  82  mm.  The 
effect  was  somewhat  lasting.  Chloroform,  10  breaths,  diminished  the  contractility 
of  both  auricle  and  ventricle,  and  caused  a  fall  in  blood-pressure  from  76  to  56  mm. 
(Tracing  made  by  Dr.  C.  C.  Lieb.) 


CAFFEINE  257 

the  vasoconstrictor  center.  A  hypodermic  injection  of  5  grains 
(0.3  gm.)  of  the  citrated  caffeine,  or  of  the  caffeine  and  sodium 
benzoate,  has  usually  resulted  in  a  slight  slowing  of  the  pulse 
with  no  measurable  effect  on  arterial  pressure.  Rarely  the 
pressure  rises  as  much  as  10  mm.  of  mercury.  Whether  or  not 
it  would  have  greater  power  than  this  to  bring  a  low  blood-pres- 
sure to  normal  is  problematic.  At  the  same  time  this  dose  of 
5  grains  sometimes  induces  undesirable  nervous  effects,  and 
cannot  be  repeated  at  very  close  intervals  without  risk  of  over- 
stimulation  of  the  cerebrum  and  spinal  cord. 

Caffeine  never  constricts  the  arteries  that  are  not  under  the 
control  of  the  vasoconstrictor  center,  viz.,  those  of  the  lungs,  the 
cerebrum,  and  the  heart.  Pilcher  and  Sollmann  find  that  the 
systemic  arteries  are  dilated  by  a  peripheral  action.  In  experi- 
mental work  the  coronary  arteries  are  regularly  dilated,  and  this 
may  be  an  important  factor  in  the  emergency  stimulation  of  the 
heart.  Cushny  suggests  that  the  dilatation  may  be  secondary 
to  the  direct  cardiac  stimulation.  The  arteries  of  the  kidneys  are 
also  dilated.  Means  and  Newburgh  have  shown  that  caffeine 
increases  the  blood  flow  in  humans;  yet  Christian  (verbal  com- 
munication] got  no  change  in  the  blood-flow  in  the  arm  after 
15  grains  (i  gm.)  given  to  students. 

Caffeine  as  a  circulatory  stimulant  is,  therefore,  purely  an 
emergency  drug,  and  not  one  to  be  used  repeatedly.  It  can  in 
no  sense  do  the  work  of  digitalis.  We  are  inclined  to  think  that 
much  of  its  apparent  value  in  conditions  of  low  blood-pressure 
is  due,  not  to  circulatory  stimulation,  but  to  stimulation  of  the 
central  nervous  system,  the  brain,  cord,  and  respiratory  center, 
the  improvement  in  muscular  tone  and  respiratory  and  mental 
vigor  being  important  in  conditions  of  general  weakness. 

Respiratory  System. — Caffeine  is  a  stimulant  of  the  respiratory 
center,  the  inspirations  being  increased  in  both  depth  and  fre- 
quency. In  the  laboratory  this  stimulation  is  best  seen  after 
the  center  has  been  depressed  by  narcotic  drugs,  such  as  mor- 
phine. From  5-grain  (0.3  gm.)  doses  subcutaneously  in  a  man 
Edsall  and  Means  obtained  an  increase  of  the  respirations,  the 
oxygen  inhaled,  the  CO2  given  off  and  the  alveolar  ventilation, 
without  effect  on  the  pulse  or  blood-pressure.  Toxic  doses  may 
induce  oppressive  breathing  from  excessive  action  of  the  respira- 
tory muscles,  and  eventually  exhaust  the  center,  causing  asphyxia 
and  death. 

Metabolism  is  increased  by  large  doses,  with  a  slight  rise  in 

temperature.     From  ordinary  amounts  of  coffee  or  tea  there  is 

no  essential  effect.     From  8  to  10  grains  (0.5-0.7  gm.)  in  a  man, 

Means,  Aub  and  Dubois,  1917,  find  a  distinct  increase  in  the  basal 

17 


258  PHARA1ACOLOGY   AND   THERAPEUTICS 

metabolism  with  no  significant  change  in  pulse-rate,  respiratory 
quotient,  proportions  of  the  various  food-stuffs  metabolized,  and 
the  percentage  of  heat  lost  through  evaporation.  Benedict 
obtained  a  distinct  retention  of  nitrogen,  and  "fears  that  caffeine 
is  not  altogether  innocuous." 

Excretion  is  fairly  rapid.  Caffeine  tends  to  lose  its  methyl 
groups  as  it  passes  through  the  body,  with  the  formation  of 
dimethyl  and  monomethyl  xanthines,  xan thine,  and  urea;  and 
these,  with  perhaps  some  unchanged  caffeine,  are  excreted  in 
the  urine.  According  to  most  investigators  there  is  no  increase 
in  the  excretion  of  uric  acid  in  health;  but  Schittenhelm  (1910) 
says  it  is  increased,  and  S.  R.  Benedict  (1916)  and  Mendel  and 
Wardell  (1917)  find  a  definite  increase  proportioned  to  the  amount 
of  caffeine  ingested.  In  chronic  gout  Hess  and  Schmoll,  and  also 
Strauss,  have  determined  that  both  caffeine  and  theobromine 
increase  the  uric  acid.  In  Strauss's  case  with  gout  in  fingers  and 
knees,  a  diet  of  2  liters  of  milk,  300  gm.  of  bread,  and  40  gm.  of 
butter  gave  an  average  uric-acid  excretion  of  0.363  gm.  per  day. 
On  the  addition  of  2  gm.  caffeine  (a  very  large  amount)  to  the 
day's  dietary  the  uric  acid  rose  to  0.621  gm. 

Kidneys. — Caffeine  is  a  drug  frequently  employed  in  the 
physiologic  investigation  of  the  kidneys,  and  these  investigations 
have  at  the  same  time  enlarged  our  knowledge  of  the  pharma- 
cology of  caffeine.  It  is  strongly  diuretic,  producing  diuresis 
in  the  isolated  kidney  just  as  well  as  in  the  intact  animal,  and  in 
the  latter  whether  general  blood-pressure  is  raised  or  not;  its 
diuresis  is  therefore  not  due  to  changes  in  the  general  circulation. 
Moreover,  local  dilatation  of  the  arterioles  is  not  the  essential 
factor,  though  usually,  as  measured  in  an  oncometer,  the  kidney  is 
enlarged  during  the  diuresis  and  the  arterioles  are  dilated.  For 
diuresis  goes  on  even  if  the  kidney  is  incased  in  a  plaster  cast  so 
that  it  cannot  expand;  and  there  are  cases  in  which,  even  when 
it  dilates  the  arterioles,  caffeine  produces  no  diuresis.  Rich- 
ards and  Plant,  in  perfusion  of  the  kidney  under  conditions  in 
which  the  blood  flow  was  kept  constant  and  independent  of  the 
action  of  the  drug,  observed  diuresis. 

To  compare  urine  with  the  blood  from  which  it  is  derived,  a 
solution  of  the  dialyzable  substances  of  the  blood  in  the  propor- 
tions in  which  they  occur  in  the  blood  is  filtered  through  an  animal 
membrane,  and  the  filtrate  diluted  with  distilled  water  until  it  has 
the  same  content  of  urea  as  the  urine.  In  this  fluid  it  is  found 
that  the  proportion  of  sulphate  and  phosphate  is  somewhat 
more  than  in  the  urine,  and  the  proportion  of  sodium  chloride  is 
considerably  more  (Loewi).  This  points  to  a  difference  in  the 
degree  of  reabsorption  of  the  different  salts  by  the  kidney  tubules. 


CAFFEINE 


259 


the  chloride  being  reabsorbed  readily,  the  sulphate  and  phos- 
phate with  more  difficulty,  and  the  urea  with  the  greatest  diffi- 
culty of  all.  In  caffeine  diuresis  Loewi  finds  that  the  more 
active  it  is,  the  more  nearly  does  the  proportion  of  chlorides  to 
urea  in  the  urine  approach  their  proportion  in  the  blood,  a  condi- 
tion that  might  be  expected  if  the  glomerular  fluid  fails  to  be 


Fig.  34. — Normal  dog:  I,  Drops  of  urine.  II,  Kidney  volume.  Ill,  General 
arterial  pressure:  a,  Before  caffeine;  b,  fourteen  minutes  after  caffeine  (from 
Pearce,  Hill,  and  Eisenbrey). 

subjected  to  the  normal  resorption  as  it  passes  through  the 
tubules.  It  would  seem,  then,  that  caffeine  may  perform  part 
of  its  action  as  a  diuretic  by  lessening  the  reabsorptive  power  of 
the  tubule  cells,  though  it  may  be  that  reabsorption  fails  to  take 
place  merely  as  the  result  of  the  increased  secretory  activity  of 
the  tubule  cells. 

Pearce,  in  his  studies  of  experimental  acute  nephritis,  found 


260 


PHARMACOLOGY   AND   THERAPEUTICS 


that  in  tubular  nephritis  caffeine  may  cause  dilatation  of  the 
renal  vessels,  so  that  the  kidney  volume  is  increased  as  much  as 
in  a  normal  kidney,  yet  without  producing  diuresis.  And  in  one 
of  his  experimental  animals  caffeine  caused  abundant  diuresis 
without  producing  any  increase  in  the  volume  of  the  kidney,  i.  e., 
without  dilatation  of  the  vessels.  In  uranium  nephritis  there 


b  c 

Fig.  35. — Dog  after  vascular  nephritis  produced  by  arsenic:  a,  Before  caffeine; 
b,  eight  minutes  after  caffeine;  c,  twenty-two  minutes  after  caffeine.  I,  Drops 
of  urine.  II,  Volume  of  kidney.  Ill,  General  arterial  pressure  (from  Pearce, 
Hill,  and  Kisenbrey). 


was  a  stage  in  which  caffeine,  sodium  chloride,  sodium  sulphate) 
urea,  and  dextrose  all  produced  vascular  dilatation,  yet  caffeine 
was  the  only  one  that  produced  diuresis.  His  inference  was  that 
the  diuresis  resulted  from  stimulation  of  the  tubule  cells,  which 
are  not  affected  by  the  other  substances. 

These  experiments,  with  many  others  of  a  like  nature,  seem 


CAFFEINE  26l 

to  indicate  that  the  diuresis  of  caffeine  is  not  at  all  through  a 
circulatory  action,  but  is  due  to  a  direct  action  of  the  caffeine 
on  the  cells  of  the  renal  tubules.  (See  also  under  Diuretics.) 
But  whether  the  action  is  stimulation  of  the  tubule  cells  or  interfer- 
ence with  reabsorption,  or  both,  has  not  been  finally  determined. 

In  caffeine  diuresis  there  is  increased  excretion  of  certain  sub- 
stances that  are  known  to  be  excreted  by  the  tubule  cells,  as 
urinary  pigment  and  creatinin.  Salant  and  Ringer  (1912)  find 
the  latter  increased  100  per  cent,  or  more  in  rabbits. 

As  with  other  diuretics,  the  more  water  there  is  in  the  body, 
the  more  readily  is  diuresis  produced.  V.  E.  Henderson  has 
shown  that  when  the  body  is  poor  in  water,  caffeine  fails  as  an 
excitant  to  secretion,  though  it  brings  about  the  usual  dilatation 
of  the  renal  arterioles.  But  caffeine  is  strongly  diuretic,  for 
Rafael  found  that  i\  grains  of  caffeine  with  1000  c.c.  of  water 
in  a  day  increased  his  urine  42  per  cent,  over  that  from  1000  c.c. 
of  water  without  the  caffeine. 

It  is  of  interest  that  caffeine  increases  peristalsis  in  the  ureters, 
for  this  alone  during  a  short  experimental  period  may  favor  the 
urine  flow. 

Toxicology. — As  coffee  and  tea  are  employed  so  extensively 
as  beverages,  mild  caffeine  poisoning  is  usually  seen  from  the  use 
of  these,  rather  than  from  the  medicinal  use  of  caffeine. 

Acute  Poisoning. — (a)  When  a  moderate  overdose  of  caffeine 
is  taken,  as  two  or  three  times  the  accustomed  amount  of  coffee 
or  tea,  the  brain  and  cord  become  overactive,  and  there  are 
increased  reflex  irritability,  increased  motor  activity,  and  impair- 
ment of  the  mental  power  because  ideas  follow  one  another  so 
rapidly  as  to  prevent  concentration  of  thought.  The  patient 
cannot  concentrate  his  attention,  and  is  excitable,  restless,  and 
unable  to  sit  quietly.  His  arm  and  leg  muscles  or  face  muscles 
may  twitch,  and  he  may  feel  gastric  discomfort,  with  oppression 
about  the  heart  and  palpitation.  His  breathing  may  be  deep, 
but  oppressive. 

The  treatment  consists  of  rest,  with  bromides  or  other  central 
sedatives.  Sollmann  and  Pilcher  found  that  alcohol  increased 
the  toxicity  of  poisonous  amounts  of  caffeine,  though  caffeine 
does  not  increase  the  toxicity  of  alcohol. 

(b]  With  marked  toxic  doses  there  may  be  vomiting,  convul- 
sions, weak  and  irregular  heart,  low  arterial  pressure,  and  col- 
lapse. Death  takes  place  usually  from  failure  of  the  heart 
muscle,  but  may  be  due  to  exhaustion  of  the  respiratory  center. 
One  case  of  death  was  reported  by  Allard  in  1904,  and  the  author 
has  seen  two  probable  instances  in  cardiac  cases.  One  of  our 
own  students  took  two  teaspoonfuls  of  pure  citrated  caffeine 


262  PHARMACOLOGY   AND   THERAPEUTICS 

instead  of  effervescing  citrated  caffeine.  He  went  into  collapse 
and  later  vomited  several  times.  He  was  very  anxious  and  ner- 
vous, and  his  heart  remained  weak  and  irritable,  so  that  he 
could  not  leave  his  bed  for  seventeen  days.  He  continued  to  be 
excessively  nervous,  and  suffered  from  insomnia  for  many  months. 

The  treatment  of  severe  poisoning  is  that  for  collapse.  Espe- 
cially necessary  is  absolute  repose.  Because  of  the  exhaustion  of 
the  centers,  drugs  are  contraindicated.  Saline  irrigations  may 
be  of  use  to  promote  elimination  by  the  kidneys. 

Chronic  poisoning  is  a  state  reached  by  excessive  daily  in- 
gestion  of  tea  or  coffee.  It  is  prone  to  show  in  digestive  disturb- 
ances, cardiac  neuroses,  nervousness,  insomnia,  and  morning 
headache,  relieved  by  coffee.  Asthenopia,  amblyopia,  nystag- 
mus, ataxia,  and  increased  reflexes  are  reported. 

Therapeutics. — i.  As  a  central  stimulant  to  counteract  the 
depression  of  the  respiratory,  cerebral,  and  spinal  centers,  and 
the  loss  of  tone  of  the  muscles  in  collapse,  especially  that  result- 
ing from  narcotic  drugs,  as  chloral,  morphine,  alcohol,  or  ether. 

2.  As  a  respiratory  stimulant  in  edema  of  the  lungs  and  de- 
pression of  the  respiration. 

3.  As  a  stimulant  or  tonic  in  convalescence  from  acute  dis- 
ease, as  after  influenza  or  pneumonia,  in  nervous  exhaustion,  in 
conditions  of  mental  and  physical  weariness,  and  in  depressed 
states  of  the  mind. 

4.  As  a  diuretic  in  dropsy  or  in  any  condition  in  which  in- 
creased urination  is  desired.     In  inflammatory  conditions  of  the 
kidneys  the  effect  depends  upon  the  amount  of  kidney  tissue  that 
is  still  functional. 

5.  Perhaps  as  an  emergency  heart  stimulant. 

6.  In  the  night  dyspnea  of  heart  cases.     Christian  found  that 
a  dose  at  bedtime  was  followed  by  better  breathing  and  sleep. 

It  is  frequently  given  with  drugs  like  acetanilid  and  phenac- 
etin,  because  of  an  erroneous  idea  that  it  will  prevent  the  depres- 
sion that  these  sometimes  cause.  But  the  studies  of  Hale  in  the 
laboratory  of  Public  Health  and  Hygiene  at  Washington  have 
shown  that  the  toxicity  of  acetanilid  and  antipyrine  are  increased 
by  caffeine.  As  a  matter  of  fact,  many  of  the  cases  of  acute 
acetanilid  poisoning  have  occurred  from  mixtures  which  contained 
caffeine.  (See  Antipyretics.) 

In  the  employment  of  caffeine  in  therapeutics,  three  things 
must  always  be  borne  in  mind,  viz.:  (i)  It  strongly  stimulates 
the  cerebral  cortex,  so  that  a  few  doses  may  result  in  an  excitable 
nervous  condition,  with  alert  mind  and  complete  inability  to 
sleep,  at  a  time  when  an  inactive  mind  and  sleep  may  be  the 
greatest  necessities  of  the  patient.  What  Mackenzie  says  of  the 


CAFFEINE   ALLIES  263 

treatment  of  heart  disease  is  especially  to  be  noted,  viz. :  "What- 
ever the  form  the  heart  failure  may  assume,  sleep  is  essential. 
It  may  be  taken  as  an  axiom  that  if  the  patient  does  not  get 
sufficient  sleep  he  will  never  get  well."  (2)  It  stimulates  the 
perceptions,  and  so  may  increase  a  patient's  suffering  and  the 
appreciation  of  his  sick  condition;  in  very  sick  patients  a  condi- 
tion of  apathy  is  better.  (3)  Its  dose  is  uncertain,  as  there  is  a 
great  difference  in  individual  susceptibility  to  the  drug,  and  the 
tea  and  coffee  habits  establish  varying  degrees  of  tolerance.  It 
is  a  well-known  fact  that  one  person  will  sleep  well  and  experi- 
ence no  discomfort  after  several  cups  of  tea  or  coffee,  while 
another  may  be  kept  awake  or  have  palpitation  of  the  heart  from 
one  cup.  A  cup  of  coffee  contains  from  i  to  2  grains  of  caffeine; 
therefore  5  grains  of  citrated  caffeine  every  four  hours,  as  I  have 
seen  prescribed,  would  equal  a  cup  of  strong  coffee  every  four 
hours  all  day  and  perhaps  for  several  days.  This  would  be  a 
large  amount  for  one  who  is  healthy,  even  if  not  especially  sus- 
ceptible to  caffeine ;  and  it  is  a  poisonous  quantity  for  one  who  is 
sick  and  is  susceptible.  Powerful  remedies  to  which  persons 
show  marked  variations  in  susceptibility  should  have  very  little 
employment  in  medicine,  because  one  cannot  calculate  in  advance 
the  probable  dose  that  will  give  the  desired  effect.  More- 
over, tea  and  coffee  are  so  much  used  that  caffeine  has  often  lost 
its  influence  to  a  greater  or  less  degree.  These  three  things, 
then,  must  be  remembered: 

1.  Caffeine  promotes  wakefulness  and  nervousness. 

2.  It  increases  the  perceptions. 

3.  Its  dose  is  uncertain,  because  of  marked  variations  in 
individual  susceptibility . 

From  large  doses  in  cases  of  myocarditis  Taylor  reports 
nausea,  vomiting,  headache,  restlessness,  and  insomnia. 

Administration. — Ordinarily,  coffee  or  tea  may  be  employed, 
or  the  citrated  caffeine  given  in  i -grain  tablet  triturates.  In 
collapse,  hot  strong  coffee  may  be  given  by  mouth  or  by  rectum; 
or  the  salicylate  or  benzoate  of  sodium  with  caffeine  may  be 
given  hypodermatically. 

CAFFEINE   ALLIES 

Theobromine,  occurring  in  chocolate  to  the  extent  of  0.3  to 
2  per  cent.,  and  theophylline,  which  occurs  in  minute  quantities 
in  tea  leaves,  but  is  manufactured  synthetically  for  the  market, 
are  isomeric  dimethylxanthines. 

Theobromine  stimulates  both  cardiac  and  voluntary  muscles 
to  some  extent,  and  has  the  diuretic  power  of  caffeine.  But  it  is 
preferred  as  a  diuretic  because  it  lacks  the  undesirable  central 


264  PHARMACOLOGY  AND   THERAPEUTICS 

effects.  For,  having  no  vasoconstrictor  action  and  but  little 
stimulating  effect  upon  the  brain,  it  may  be  given  in  much  larger 
closes  without  the  production  of  wakefulness.  The  dose  is 
10  grains  (0.6  gm.),  given  in  capsule  or  powder  three  or  four 
times  a  day.  As  it  is  insoluble  and  but  slowly  absorbed,  its 
soluble  combination  with  sodium  salicylate,  theobromine  sodio- 
salicylate,  known  also  by  the  proprietary  name,  diuretin,  is  pre- 
ferred. Its  dose  is  twice  that  of  theobromine.  We  have  many 
times  noted  a  rise  to  between  200  and  300  ounces  in  the  urine 
flow  of  dropsical  patients  after  theobromine  or  diuretin.  Chris- 
tian says  that  this  is  an  effect  seen  in  cardiac  dropsy  rather  than 
renal  dropsy,  but  the  author  has  seen  it  also  in  true  kidney  cases. 
In  one  recent  kidney  case  with  high  blood-pressure,  retinal 
changes,  low  phthalein  output  and  low  Ambard  urea  coefficient, 
the  urine  reached  the  phenomenal  amount  of  300  ounces  in 
twenty-four  hours;  and  the  output  continued  high  during  seven 
days'  administration  of  the  drug. 

Theophylline  (theocine)  has  the  same  action  and  dose,  but  it 
is  more  irritating  to  the  stomach,  so  that  nausea  is  not  infrequent, 
and  it  has  some  of  the  central  effects  of  caffeine  (Thomas). 
Theocin-acet-sodium  is  a  soluble  salt  of  this  alkaloid.  In  the 
author's  experience  both  mouth  and  intravenous  doses  have  re- 
sulted in  active  diuresis.  Dose,  7^  grains  (0.5  gm.),  three  or  four 
times  a  day. 

THEOBROMINE   AND   CAFFEINE   BEVERAGES 

The  ones  that  are  in  more  or  less  universal  use  among  civilized 
people  are  coffee,  tea,  and  chocolate.  Most  of  our  coffee  comes 
from  Brazil,  our  tea  from  Japan,  China,  and  India,  and  our 
chocolate  from  the  West  Indies.  The  use  of  caffeine-bearing 
parts  of  plants  as  beverages  in  various  parts  of  the  world  has 
already  been  spoken  of. 

Coffee. — The  dried  coffee-seeds  are  roasted  and  then  ground 
before  use.  Roasted  coffee  contains  0.6  to  2  per  cent,  of  caf- 
ieine,  a  small  amount  of  caffeol  (caff eon),  and  a  large  amount 
of  tannic  acid.  Caffeol  is  an  empyreumatic  volatile  oil  (a  mix- 
ture) developed  in  the  roasting.  It  is  the  source  of  the  flavor 
and  aroma  of  the  coffee,  and  is  so  penetrating  that  a  single 
drop  of  it  will  fill  a  room  with  the  coffee  odor.  The  tannic  acid 
of  coffee,  caffeotannic  acid,  unlike  that  of  tea,  does  not  precipitate 
albumin,  gelatin,  or  alkaloids,  and  is  not  astringent.  It  is  con- 
sequently of  no  use  as  a  precipitant  in  poisoning  by  alkaloids. 
It  constitutes  undesirable  extractive  matter,  however,  in  coffee, 
for  so  much  colloid  matter  tends  to  check  digestion  and  to  re- 
tard absorption. 


THEOBROMINE  AND  CAFFEINE  BEVERAGES        265 

The  beverage  is  prepared  by  pouring  boiling  water  over 
freshly  ground  coffee  and  allowing  it  to  steep  for  a  few  minutes; 
or  by  permitting  boiling  water  to  percolate  through  the  ground 
coffee  in  a  special  coffee-pot.  The  coffee  should  not  be  boiled, 
as  boiling  drives  off  the  flavoring  volatile  oil  and  makes  a  heavier 
decoction  of  the  extractive  matter. 

Tea. — This  is  made  from  the  young  leaves,  which  are  prepared 
by  a  process  of  rolling,  fermenting,  and  drying.  The  constitu- 
ents are  i  to  4  per  cent,  of  caffeine,  a  minute  amount  of  theo- 
phylline,  0.6  per  cent,  of  volatile  oil,  which  imparts  the  flavor  and 
odor,  and  a  large  amount  of  tannic  acid  of  the  kind  that  precipi- 
tates gelatine,  albumin,  and  alkaloids,  and  is  strongly  astringent. 
India  and  Ceylon  teas  contain  much  more  tannic  acid  than  China 
teas  (Luke).  Green  tea  is  made  from  the  younger  leaves.  It 
contains  more  tannic  acid,  more  volatile  oil,  and  less  caffeine  than 
black  tea,  so  is  less  stimulating  and  more  astringent.  In  a 
number  of  samples  Bannister  found  that  the  black  teas  averaged 
3.24  per  cent,  of  caffeine  and  16.4  per  cent,  of  tannic  acid,  while 
the  green  teas  averaged  2.33  per  cent,  of  caffeine  and  27.14  per 
cent,  of  tannic  acid.  These  figures  do  not  correspond  with  those 
of  Spencer,  who  found  4.8  to  15.8  per  cent,  of  tannic  acid  in 
various  teas.  It  is  claimed  that  in  the  preparation  of  the  tea 
leaves  for  the  market  about  half  the  tannic  acid  is  lost. 

The  beverage  should  be  made  by  pouring  boiling  water  upon 
the  leaves  and  allowing  them  to  steep  from  two  to  five  minutes. 
The  tea  should  not  be  boiled,  as  this  hastens  the  solution  of  the 
tannic  acid  and  drives  off  the  flavoring  oil.  As  the  tannic  acid 
and  coloring-matter  dissolve  but  slowly  in  water  that  is  not 
boiling,  a  fair  percentage  of  these  may  be  left  behind  if  the  tea 
is  soon  poured  off  the  leaves.  If  it  is  allowed  to  steep  too  long, 
the  beverage  becomes  more  deeply  colored  and  richer  in  tannic 
acid.  The  tea  which  stands  all  day  long  in  the  tea-pot  and  is 
drunk  cold  by  the  inveterate  tea-drinker  is  essentially  a  solution 
of  tannic  acid  which  would  effectively  tan  hides  into  leather. 

The  amount  of  tea  used  in  making  a  cup  represents  i  to  2 
grains  (0.06-0.12  gm.)  of  caffeine,  and  the  coffee  per  cup  if 
to  3  grains  (0.1-0.2  gm.),  but  always  some  of  the  caffeine  is 
left  behind.  Tea  leaves  contain  more  of  the  caffeine  than  coffee, 
but  much  less  tea  is  used  per  cup. 

Pharmacologic  Action. — Besides  the  caffeine  action,  coffee 
derives  some  of  its  properties  from  the  empyreumatic  oil,  caffeol. 
This  is  somewhat  stimulating  to  the  cerebrum,  but  in  the  alimen- 
tary tract  is  a  local  irritant.  Pincussohn  has  found  that  coffee 
results  in  a  prompt  increase  in  the  amount  and  the  acidity  of  the 
gastric  juice;  and  it  is  a  well-known  fact  that  on  the  intestines 


266  PHARMACOLOGY   AND   THERAPEUTICS 

the  beverage  acts  as  a  laxative,  promoting  peristalsis.  These 
factors  may  not  be  of  importance  in  normal  persons,  but  they 
become  so  in  hyperesthetic  states  of  the  stomach  (hyperchlor- 
hydria,  hypersecretion,  and  gastrosuccorhea)  and  in  diarrhea, 
so  that  coffee  may  be  contraindicated. 

Tea  seems  to  have  a  more  immediate  stimulating  effect, 
either  because  of  its  volatile  oil  or  because  absorption  is  more 
rapid.  In  "strong"  tea  the  local  action  in  the  alimentary  tract 
is  due  chiefly  to  its  tannic  acid.  This  tends  to  lessen  gastric 
secretion,  to  retard  absorption,  and  to  induce  constipation,  so 
that  tea  which  is  strong  in  tannic  acid  may  decidedly  interfere 
with  digestion.  But  because  it  contains  less  extractive  matter 
than  coffee,  properly  made  tea — i.  e.,  tea  without  much  tannic 
acid — is  less  disturbing  to  the  stomach  than  coffee.  In  nervous 
dyspepsia  both  tea  and  coffee  are  harmful  because  of  the  caffeine 
effect  on  the  nervous  system. 

Coffee  and  tea  are  not  nutritive  in  themselves,  and  require 
no  digestive  process  for  their  absorption.  But  the  addition  of 
milk  or  cream  and  sugar  changes  them  into  food.  In  tea  the 
tannic  acid  precipitates  the  coagulable  protein  of  the  milk,  but 
this  precipitate  digests  in  the  gastric  juice.  In  some  instances 
the  milk  and  cream  have  a  desirable  effect  by  lessening  the  local 
irritant  action  in  the  stomach,  and  by  retarding  the  absorption 
of  the  caffeine. 

As  therapeutic  amounts  of  caffeine  are  directly  antidotal  to 
the  cerebral  effects  of  alcohol,  the  after-dinner  demi-tasse  may 
have  a  special  use  when  wine  has  been  drunk  at  the  dinner.  As 
a  hot  drink  which  contains  a  volatile  oil  it  may  also  be  slightly 
stimulating  to  the  stomach.  However,  its  reputation  as  an  aid 
to  digestion  depends  more  on  habit  than  upon  any  intrinsic  power 
in  the  stomach. 

The  coffee  and  tea  habits  are  common  among  brain-workers 
(students,  writers,  etc.)  and  those  who  must  remain  awake  at 
night  (nurses,  journalists,  etc.).  The  tea  habit  is  prevalent 
in  some  localities,  the  afternoon  "cup  that  cheers  but  not  in- 
ebriates" being  employed  to  brighten  the  gossip  of  an  after- 
noon call  or  to  remove  the  feelings  of  tiredness.  In  the  southern 
United  States  the  "kola  habit"  is  prevalent,  a  proprietary  drink 
being  in  great  favor.  Much  coffee  or  tea  may  result  in  nervous- 
ness and  insomnia,  with  cardiac  and  digestive  neuroses;  but  in 
such  a  case  stoppage  of  the  beverage  will  usually  be  sufficient  to 
restore  the  patient  to  normal  in  a  short  time.  (See  Chronic 
Caffeine  Poisoning,  p.  262.)  In  insomnia  caffeine  drinks  must 
not  be  taken  lute  in  the  day. 

Tolerance. — The   variations   in   individual   susceptibility   to 


THEOBROMINE  AND  CAFFEINE  BEVERAGES        267 

tea  and  coffee  are  marked,  one  person  being  wakeful  and  restless 
and  mentally  stimulated  by  a  single  cup  of  coffee  or  tea,  while 
another  will  be  unaffected  by  several  cups.  In  many  instances 
a  limited  toleration  is  set  up,  so  that  the  amount  of  tea  or  coffee 
may  be  steadily  increased  for  a  time;  but  it  is  an  interesting  fact 
that  long-continued  excessive  drinking  of  tea  or  coffee  sometimes 
results  in  a  condition  of  increased  susceptibility  which  may  per- 
sist for  months  or  even  years.  So  that  one  who  formerly  regu- 
larly drank  several  cups  of  coffee  a  day  with  apparent  impunity 
finds  himself  unable  to  drink  more  than  one  or  two  cups  without 
feeling  the  bad  effects.  The  habitual  cup  of  coffee  or  tea  seems 
to  have  little  if  any  diuretic  effect. 

The  drinking  of  tea  and  coffee  is  so  common,  and  their  harm- 
ful effects  are  so  evident,  that  physicians  are  prone  to  proscribe 
these  beverages  rather  than  to  prescribe  them. 

Before  leaving  this  subject  I  should  like  to  say  to  every  stu- 
dent that  if  he  gets  into  a  state  in  which  night  after  night  he 
cannot  work  without  coffee,  he  is  drawing  upon  his  reserves,  so 
that  when  he  needs  to  make  a  spurt  he  will  be  unable  to  do  so. 
In  such  a  case  what  he  really  needs  to  clear  his  brain  is  a  short 
period  of  rest  from  excessive  study,  with  open-air  exercise  and 
good  sleep.  If  he  is  to  have  some  special  test  of  his  knowledge, 
such  as  an  examination,  then  a  cup  or  two  of  coffee  may  enable 
him  to  do  his  best  intellectual  work,  while  an  excessive  amount 
will  only  make  him  nervous  and  unable  to  think  clearly. 

Chocolate. — Chocolate  is  the  paste  made  from  the  ripe  seeds  of 
the  chocolate  plant,  Theobroma  cacao,  after  they  have  been  sweated, 
dried,  roasted,  and  deprived  of  their  shells  (the  so-called  "cocoa 
nibs").  The  sweating  or  fermentation  process  removes  practi- 
cally all  the  tannic  acid  and  some  of  a  bitter  substance  which  is 
present  in  the  ripe  seed,  and  the  roasting  brings  out  the  chocolate 
flavor.  Chocolate  contains  from  0.3  to  2  per  cent,  of  theobro- 
mine  (according  to  some  authorities,  also  caffeine  up  to  0.35  per 
cent.),  10  per  cent,  of  starch,  15  per  cent,  of  vegetable  protein, 
and  30  to  50  per  cent,  of  a  peculiar  fat  which  is  known  as  cocoa- 
(cacao)  butter.  (See  Fats,  Part  I.)  Pure  chocolate  is  not 
pleasant  to  the  taste,  so  for  eating  and  drinking  it  is  regularly 
sweetened  with  sugar  and  often  flavored  with  vanilla.  It  is 
highly  nutritive,  and  has  been  shown  by  Weissmann,  Zuntz,  and 
others  to  be  almost  completely  digestible,  but  the  fat  acts  in  the 
stomach  to  retard  both  the  secretion  of  gastric  juice  and  the  motor 
functions,  i.  c.,  the  emptying  of  the  stomach,  so  chocolate  cannot 
be  taken  in  large  quantities.  Neumann  replaced  a  fixed  allow- 
ance of  bread,  sausage,  pork,  sugar,  and  cheese  with  an  amount 
of  cocoa  and  cocoa-butter  of  equal  caloric  value.  The  diet  was 


268  PHARMACOLOGY   AND   THERAPEUTICS 

moderately  satisfactory,  but  he  developed  a  severe  headache 
which  he  attributed  to  the  theobromine. 

Cocoa  is  a  powdery  preparation,  made  from  chocolate  by 
removing  a  portion  of  the  cocoa-butter  by  hydraulic  pressure, 
with  or  without  heat.  The  dried  residue  is  ground  to  a  very 
fine  powder,  so  that  it  may  be  more  readily  mixed  with  water. 
The  proportion  of  the  theobromine  in  cocoa  is  thus  somewhat 
higher  than  in  chocolate,  while  the  fat  is  less,  constituting  only 
15  to  30  per  cent.  Inferior  cocoas  are  made  by  diluting  the  choc- 
olate with  starch,  thus  reducing  the  theobromine  as  well  as  the 
fat.  The  so-called  Dutch  process  is  one  of  partial  saponification 
of  the  fat  with  an  alkali,  to  make  it  miscible  with  water. 

•The  beverage  "cocoa"  is  made  by  boiling  the  cocoa  powder 
with  water  or  milk  for  at  least  five  minutes,  so  that  its  starch 
may  be  properly  hydrolyzed;  otherwise  it  is  nothing  but  a  crude 
mixture  from  which  the  powder  tends  to  separate.  When  it  is 
made  with  milk  and  is  sweetened  with  sugar,  it  has  a  high  food 
value;  a  cupful  of  such  a  beverage,  prepared  with  about  10  grams 
of  cocoa,  giving  a  nutritive  value  of  perhaps  250  calories.  Such 
a  drink  may  sometimes  be  taken  by  invalids  for  its  food  value. 

Chocolate  is  sometimes  made  into  a  beverage,  but  it  contains 
so  much  fat  and  requires  so  much  sugar  that  it  is  rich  and  sweet 
and  is  heavy  in  the  stomach.  It  is  not  suited  for  invalids. 

Cocoa  and  chocolate  have  the  properties  of  theobromine, 
but  kidney  tolerance  is  soon  established,  so  that  no  "diuresis" 
results  from  the  habitual  cup. 

NUX  VOMICA 

Nux  vomica  is  the  dried  ripe  seed  of  Strychnos  Nux  vomica 
(Fam.  Loganiacea),  yielding,  when  assayed,  not  less  than  2.5 
per  cent,  of  alkaloids.  It  is  native  in  India,  Cochin-China, 
and  Australia. 

Constituents. — The  alkaloids,  strychnine  and  brucine,  the 
two  being  present  in  more  or  less  equal  quantities.  They  exist 
in  combination  with  igasuric  acid,  an  acid  which  makes  a  dark 
greenish  color  with  ferric  salts. 

Preparations  and  Doses. — /.  Of  Nux  Vomica. — All  are  as- 
sayed. 

Nux  vomica 2.5  percent,  of  alkaloids.  .  i  grain  (0.06  gm.). 

Extract 16  per  cent |  grain  (o.oi  gm.). 

Fluidextract 2.5  per  cent i  minim  (0.06  c.c.). 

Tincture 0.25  per  cent 10  minims  (0.6  c.c.). 

Ten  minims  of  the  tincture  of  nux  vomica  must  assay  to  con- 
tain not  less  than  -fa  grain  (0.0012  gm.)  of  alkaloid,  equiva- 


NUX   VOMICA  269 

lent  to  about  5V  grain  (0.0008  gm.)  each  of  strychnine  sulphate 
and  brucine  sulphate. 

//.  Of  Strychnine. — The  official  salts  are  the  nitrate,  soluble 
in -42  parts  of  water  and  in  150  of  alcohol,  and  the  sulphate, 
soluble  in  32  parts  of  water  and  in  81  of  alcohol.  Dose  3V 
grain  (0.0015  gm.).  The  maximum  beginning  dose  is  3V  grain 
(0.003  gm-)-  According  to  their  molecular  weights,  the  nitrate 
contains  84  per  cent,  of  pure  strychnine,  and  the  sulphate  77  per 
cent.  In  dry  air  the  sulphate  tends  to  become  stronger  by  the 
loss  of  its  water  of  crystallization,  while  the  nitrate  is  per- 
manent. 

Much  used  non-pharmacopceial  preparations  of  strychnine  are : 

Citrate  of  iron  and  strychnine,  i  per  cent.  Dose,  2  grains 
(0.13  gm.). 

Elixir  of  the  phosphates  of  iron,  quinine,  and  strychnine.  Dose, 
i  dram  (4  c.c.)  =  gV  grain  (o.ooi  gm.)  strychnine  and  T7S 
grain  quinine. 

Syrup  of  the  phosphates  of  iron,  quinine,  and  strychnine.  Dose, 
i  dram  (4  c.c.)  =  ^V  grain  (0.0008  gm.)  strychnine  and  if 
grains  quinine. 

Compound  syrup  of  the  hypo  phosphites.  Dose,  2  drams  (8 
c.c.)  =  strychnine,  ^  grain  (o.ooi  gm.),  and  quinine,  y^ 
grain. 

Compound  laxative  pills — aloin,  |  grain,  extract  belladonna, 
|  grain,  ipecac,  TV  grain,  strychnine,  the  pure  alkaloid, 
T£0  grain  (0.0005  gm-)- 

Pharmacologic  Action. — On  man  brucine  has  the  same  type 
of  action  as  strychnine,  but  it  has  been  estimated  to  be  only 
sV  to  |  as  strong,  hence  the  strychnine  practically  represents 
the  nux  vomica  action. 

Alimentary  Tract. — The  taste  is  intensely  bitter — so  bitter, 
indeed,  that  it  is  perceptible  in  a  solution  of  i  part  in  1,000,000 
of  water.  As  the  result  of  the  bitterness  there  is  a  reflex  flow  of 
saliva,  and  the  drug  has  the  effect  of  a  bitter  upon  the  taste- 
buds.  (See  Bitters.) 

After  absorption  into  the  blood,  the  strychnine  effect  upon 
the  spinal  cord  results  in  an  increase  in  the  tone  of  the  muscles 
of  the  stomach  and  intestines,  and  probably  in  an  increase  of 
reflex  secretory  activity. 

Absorption  is  rapid,  especially  from  the  intestines.  As 
reported  by  one  investigator,  convulsions  came  on  in  thirty 
minutes  after  the  injection  of  i^  grains  into  the  stomach  of  a 
cat,  while  convulsions  followed  injection  of  the  same  amount  into 
the  small  intestine  in  ten  minutes,  and  a  similar  injection  into 
the  rectum  in  seven  minutes.  Ryan  (1912)  found  absorption  of 


270  PHARMACOLOGY  AND  THERAPEUTICS 

an  aqueous  solution  quite  rapid  from  the  stomach.  He  used  the 
small  pouch  of  the  Pawlow  stomach,  so  as  to  prevent  passage  of 
the  strychnine  into  the  intestines,  while  allowing  the  normal 
motor  activity  to  go  on.  Starling  states  that  "strychnine  in- 
jected under  the  skin  of  a  limb  will  exert  its  poisonous  effects  on 
the  nervous  system  long  before  the  drug  itself  appears  in  the 
lymph  flowing  from  the  limb." 

Cerebrum. — There  is  a  slight  stimulation  of  the  intellect  and 
of  the  motor  areas,  in  kind  like  that  of  caffeine.  But  in  degree 
it  is  much  less  marked,  so  that  strychnine  is  not  a  pronounced 
intellectual  stimulant,  and  has  much  less  effect  than  caffeine  in 
opposing  sleep.  The  perceptions  are  all  stimulated,  pain  being 
more  keenly  felt,  the  senses  of  smell  and  taste  more  discriminat- 
ing, that  of  hearing  more  acute,  that  of  touch  more  sensitive. 
These  are  all  central  effects.  The  sight  is  also  rendered  more 
keen,  particularly  in  distinguishing  colors;  and  as  this  effect  is 
produced  in  only  one  eye,  if  the  drug  is  dropped  into  that  eye  or 
if  it  is  injected  into  the  immediate  vicinity  of  that  eye,  the 
strychnine  is  believed  to  act  peripherally  on  the  retinal  elements, 
which  it  reaches  through  the  lymph-spaces.  The  optic  centers 
are  also  probably  stimulated.  Through  these  two  factors,  large 
doses  of  strychnine  injected  into  the  temple,  in  partial  optic 
nerve  atrophy,  will  sometimes  bring  about  an  improvement  in 
the  sight. 

Spinal  Cord. — If  a  poisonous  dose  of  strychnine  is  admin- 
.istered  to  an  animal,  a  very  slight  stimulus,  such  as  the  prick  of 
a  pin,  a  touch,  or  the  jarring  of  the  table  upon  which  the  animal 
lies,  will  send  it  into  convulsions.  Something  has  happened  to 
make  a  tremendous  muscular  response  to  an  ordinary  stimulus. 
What  does  the  strychnine  do?  Note  the  following  experiments: 

1 .  Expose  the  sciatic  nerve  of  a  frog  and  ligate  the  rest  of  the 
limb  so  as  to  leave  the  nerve  outside  of  the  ligature.     This 
leaves  the  nervous  connections  between  the  spinal  cord  and  the 
lower  part  of  the  limb  intact,  but  cuts  off  the  limb's  circulatory 
connection  with  the  rest  of  the  body.     Inject  strychnine  into  the 
leg  below  the  ligature,  where  it  can  act  locally  on  nerve-endings 
and  nerve-trunk.     The  reflexes  are  still  intact,  because  the  nerve 
is  left  outside  of  the  ligature,  but  the  strychnine  does  not  get  to 
the  spinal  cord  because  the  circulation  is  cut  off.    The  prick  of  a 
pin  below  the  ligature  now  meets  with  just  the  usual  response; 
therefore  the  strychnine  does  not  stimulate  the   nerve-ending 
or  nerves,  either  sensory  or  motor.     If,  now,  strychnine  is  in- 
jected above  the  ligature,  the  prick  of  a  pin  below  the  ligature 
results  in  convulsions. 

2.  Poulsson's  Experiment. — Dip  a  frog  in  5  per  cent,  cocaine 


NUX  VOMICA  271 

solution  until  its  skin  is  just  anesthetized,  so  as  to  cut  off  any 
,  afferent  impulses  from  the  surface;  then  give  a  large  dose  of 
strychnine,  and  no  convulsions  result.  Now  generate  afferent 
impulses  by  stimulating  the  nerve-trunks,  and  convulsions 
follow. 

3.  Claude  Bernard's  Experiment. — Cut  the  posterior  nerve- 
roots  to  prevent  afferent  impulses  from  getting  to  the  cord, 
strychnize  the  frog,  and  no  convulsions  result.  Stimulate  the 
central  cut  end  and  convulsions  follow,  whether  the  roots  have 
been  cut  peripheral  or  central  to  the  ganglia. 

These  experiments  show — (i)  That  the  drug  does  not  act 
upon  the  peripheral  nerves  or  the  posterior  root  ganglia.  (2) 
That  it  does  not  of  itself  produce  motor  effects.  (3)  That  it 
causes  increased  motor  response  to  afferent  impulses,  i.  e.,  to 
external  stimuli. 

The  convulsions  are,  therefore,  reflex  in  nature,  the  strych- 
nine acting  on  structures  in  the  cord  itself  and  resulting  in  greatly 
increased  reflex  excitability. 

What  is  a  reflex?  If  the  eye  is  exposed  to  a  light,  the  pupil 
contracts;  if  some  irritating  dust  gets  into  the  nose,  it  causes 
sneezing.  These  are  motor  reflexes.  If  about  dinner  time  the 
appetizing  odor  of  food  is  recognized,  the  stomach  begins  to 
secrete  gastric  juice;  if  a  substance  of  bitter  taste  gets  into  the 
mouth,  the  saliva  flows.  These  are  secretory  reflexes.  In  each 
case  there  is  some  peripheral  stimulus,  these  actions  not  occurring 
otherwise,  and  the  response  is  involuntary.  A  reflex,  then,  is  an 
involuntary  secretory  or  motor  response  to  an  afferent  impulse. 

Reflex  actions  are  usually  purposeful  and  definite,  the  same 
kind  of  response  regularly  following  stimulation  at  a  given  place. 
A  piece  of  dust  on  the  conjunctiva  ordinarily  results  in  instant 
closure  of  the  eye;  a  teaspoonful  of  mustard  placed  in  the  stomach 
regularly  results  in  vomiting;  the  dipping  of  a  frog's  hind  leg  in 
acetic  acid  regularly  results  in  a  drawing  of  the  leg  away  from  the 
offending  substance  and  an  attempt  to  wipe  it  away  with  the 
other  leg.  The  afferent  impulses,  therefore,  do  not  travel  at 
random  to  any  motor  cells,  but  would  seem  to  travel  to  those 
motor  cells  which  can  produce  the  proper  purposeful  motor 
response.  That  is,  for  each  afferent  impulse  there  seems  to  be 
in  the  cord  one  particular  path  or  group  of  paths  along  which  it 
travels  to  reach  the  motor  or  secretory  cells,  this  one  path  ordi- 
narily being  open  to  it,  while  all  other  paths  are  closed  to  it.  By 
training,  certain  new  paths  are  opened  up,  or,  in  other  words, 
actions  which  are  at  first  voluntary  become  reflex,  as  in  piano- 
playing,  skating,  and  most  of  our  activities.  At  first  the  will  is 
necessary  to  insure  the  desired  response  to  the  stimulus,  as  that 


272  PHARMACOLOGY   AND   THERAPEUTICS 

the  finger  shall  strike  a  certain  key  of  the  piano  when  the  eye  sees 
a  certain  printed  note.  But  by  constant  repetition  a  path  is 
established  so  that  the  player  comes  to  strike  the  proper  key 
involuntarily  as  soon  as  the  eye  perceives  the  note. 

Reflexes  are  of  three  kinds,  viz.: 

(i)  The  simple  reflexes,  which  involve  only  one  muscle,  as 
in  winking  the  eye.  (2)  The  coordinated  reflexes,  in  which, 
during  the  contraction  of  one  set  of  muscles,  there  is  inhibition 
of  the  opposing  muscles;  these  are  the  ordinary  purposeful 
reflexes  of  our  bodies.  (3)  The  convulsive  reflexes,  which  are 
incoordinated  because  all  the  muscles  are  stimulated,  and  there 
is  no  inhibition.  Since  all  the  muscles  contract,  the  stronger 
predominate.  Convulsive  reflexes  are  exaggerated,  purposeless, 
and  harmful,  and  are  due  to  some  derangement  of  coordination. 

How  does  strychnine  produce  convulsive  reflexes?  Baglioni 
(1900)  performed  an  experiment  which  has  become  classic.  He 
exposed  the  spinal  cord  of  a  decapitated  frog  at  the  brachial 
plexus,  and  removed  the  pia  with  its  vessels  to  cut  off  circulatory 
connection  with  the  parts  of  the  cord  above  and  below.  He  then 
painted  the  denuded  area  with  a  solution  of  strychnine,  and  thus 
poisoned  the  part  of  the  cord  through  which  afferent  impulses 
from  the  fore-limb  would  have  to  pass,  but  did  not  poison  the 
rest  of  the  cord. 

1.  On  stimulating  the  hind-limb,  he  got  the  usual  normal  re- 
flex response,  the  poisoned  area  being  beyond  the  influence  of  such 
a  stimulus.     When  he  pinched  the  foot,  the  leg  was  drawn  up;  if 
he  placed  a  drop  of  acetic  acid  upon  the  leg,  the  other  leg  would 
be  drawn  up  to  wipe  it  off.     This  proved  that  the  sensory  nerves, 
the  synapses,  and  the  motor  cells  in  the  lower  part  of  the  cord 
were  unpoisoned  and  acting  normally. 

2.  But  when  he  pinched  or  pricked  one  of  the  fore-limbs  or 
dipped  it  in  acid,  there  resulted  a  convulsion  of  the  whole  body, 
both  hind-limbs  and  fore-limbs  being  involved.     In  other  words, 
when   the   afferent   impulse   passed   through   an   unstrychnized 
portion  of  the  cord,  the  response  was  the  usual  one;  but  when 
the  impulse  passed  through  a  strychnized  area,  there  was  an 
abnormal  response,  not  only  in  the  muscles  usually  affected  by 
such  an  impulse  in  an  unpoisoned  animal,  but  also  in  a  large 
number  of  the  other  muscles  of  the  body.     These  muscles  went 
into  a  convulsive  state,  whether  their  motor  cells  were  in  the 
poisoned  area  or  not.     Therefore  the  action  of  the  strychnine  is 
neither  on  the  motor  cells  themselves  nor  on  the  synapses  about 
the  motor  cells;  and  is  in  all  probability  on  either  the  intermediary 
neurons  in  the  cord  or  the  first  synapses  of  the  afferent  system. 

If  the  dose  given  is  just  a  little  less  than  enough  to  produce 


NUX   VOMICA 


273 


convulsive  twitching,  the  response  of  the  usual  muscles  is  greater 
than  normal,  but  in  the  usual  purposeful  way;  and  this  is  be- 
lieved to  be  due  to  the  greater  transmission  of  the  afferent  im- 
pulses. There  is  no  satisfactory  evidence  that  the  motor  cells 
themselves  are  stimulated. 

Hence  the  action  of  strychnine  upon  the  spinal  cord  may  be 
thought  of  as  not  only  to  facilitate  the  passage  of  afferent  im- 
pulses to  their  usual  motor  cells,  but  to  open  up  the  paths  to  the 
other  motor  cells,  so  that  the  impulses  may  reach  and  affect  cells 


A  B 

Fig.  36. — Kolliker's  schema  to  show  the  reflex  arc.  A  shows  the  posterior 
root-fiber  (black)  dividing  and  spreading  up  and  down  the  cord,  and  connecting 
with  many  motor  cells  (red)  through  its  synapses  (black  ramifications).  B  shows 
the  posterior  root-fiber  connecting  through  the  first  synapse  of  the  afferent  sys- 
tem with  an  intermediate  neuron  (green),  which  in  turn  connects  with  numerous 
motor  cells  (red)  through  its  synapses  (after  Ho  well). 

ordinarily  beyond  their  influence.  In  other  words,  strychnine 
increases  rcjlex  activity  by  facilitating  the  passage  of  afferent  im- 
pulses in  the  cord  (across  and  up  and  down  the  cord).  It  may 
directly  stimulate  the  motor  cells  themselves,  but  this  is  not 
proved . 

Sherringtons   Theory. — As  has  been  pointed  out,  a  certain 
stimulus  leads,  normally,  through  coordination,  not  only  to  con- 
traction of  a  certain  group  of  muscles,  but  also  to  relaxation  of 
the  opposing  group;  and  the  same  stimulus,  after  a  toxic  dose  of 
18 


274  PHARMACOLOGY   AND   THERAPEUTICS 

strychnine,  induces  contraction  not  only  in  the  usual  group,  but 
also  in  the  antagonists.  Therefore,  under  strong  strychnine 
stimulation  all  the  muscles  contract,  so  that,  of  two  sets  of 
opposing  muscles,  the  stronger  regularly  predominate.  For 
example,  if  an  animal  poisoned  with  strychnine  attempts  to 
open  its  mouth,  both  the  opening  and  closing  muscles  are  ex- 
cited, and  as  the  closing  muscles  are  the  stronger,  the  mouth 
becomes  all  the  more  tightly  closed.  If  a  man  under  an  excess- 
ive dose  of  strychnine  tries  to  walk,  his  gait  is  spastic,  and  his 
legs  are  more  or  less  stiff,  because  all  the  muscles  are  in  an  ex- 
citable contractile  state.  Sherrington's  belief  is  that  the  strych- 
nine overaction  is  due  to  a  change  of  the  usual  relaxation  or 
inhibition  of  the  opposing  muscles  into  contraction  or  excitation, 
and  the  will  is  in  complete  abeyance.  This  well  explains  the 
exaggerated  and  convulsive  reflexes,  and  the  spasticity,  but  not 
the  widespread  response  to  a  stimulus. 

Following  up  this  theory,  Bayliss  has  been  able  to  show  that, 
after  poisonous  amounts  of  strychnine,  stimulation  of  the  de- 
pressor nerve  will  result  in  a  rise  in  arterial  pressure,  i.  e.,  the 
depressor  nerve  is  no  longer  an  inhibitory  nerve,  but  an  excita- 
tory nerve. 

Tone. — Tone  is  a  condition  of  readiness  to  respond  to  stimu- 
lus. All  the  muscles,  both  voluntary  and  involuntary,  are  in  a 
constant  state  of  tone,  i.  e.,  they  are  in  a  condition  of  slight  con- 
traction, so  that  they  are  drawn  up  in  readiness  to  work  the 
moment  a  stimulus  comes.  One  or  two  experiments  to  determine 
the  nature  of  muscular  tone  are  of  interest: 

1.  If  a  frog  is  decapitated  and  the  sciatic  nerve  of  one  side 
cut,  the  leg  on  the  cut  side  is  more  relaxed  than  the  other  leg, 
i.  e.,  severance  of  the  leg  from  its  connection  with  the  central 
nervous  system  results  in  greater  relaxation  than  normal,  or  loss 
of  its  tone.     It  is  evident  then  that  the  tone  of  the  leg  is  due  to 
the  reception  of  stimuli  from  the  motor  cells  of  the  spinal  cord. 

2.  If  a  frog's  skin  is  anesthetized  by  immersing  the  frog  in 
5  per  cent,  cocaine  to  cut  off  external  stimuli,  or  its  posterior 
nerve-roots  cut  to  prevent  any  afferent  impulses  from  reaching 
the  cord,  there  results  marked  muscular  relaxation,  i.  e.,  loss  of 
tone  on  both  sides.     Evidently,   therefore,   tone  of  voluntary 
muscle  is,  at  least  in  great  part,  dependent  upon  the  reception  in 
the   cord   of  afferent   impulses.     Tone  is,   therefore,   largely  a 
manifestation  of  reflex  activity.     Strychnine  heightens  tone  by 
increasing  rcjkx  excitability,  and  on  this  property  most  of  the 
therapeutic  usefulness  of  strychnine  depends.     It  is  the  best  of 
our  genuine  "tonics." 

Resume. — The  therapeutic  use  of  strychnine  is  to  open  up  the 


Fig.  37.— Strychnine  sulphate.  0.2  mg.  per  kilo,  no  effect  on  circulatory  organs. 
Upper  tracing,  auricle;  middle,  ventricle;  lower,  blood-pressure;  upper  line  of 
bgures,  pulse-rate.  (Tra<  'iig  made  by  Dr.  ('.  C.  Liel).) 


NUX   VOMICA  275 

normal  paths  in  the  cord  when  they  become  clogged,  so  that  an 
afferent  impulse  can  reach  the  usual  motor  cells  with  greater 
facility.  In  other  words,  it  is  to  increase  tone  and  the  usual 
purposeful  reflexes.  Therapeutically,  there  is  no  desire  to  have 
an  impulse  affect  other  cells  than  the  usual  ones.  The  poisonous 
action  is — (i)  To  open  widely  the  regular  paths  to  motor  cells 
(overtone);  (2)  to  interfere  with  coordination  by  changing  the 
normal  inhibition  of  opposing  muscles  into  excitation  (spasticity) ; 
and  (3)  to  open  up  great  numbers  of  new  paths,  so  that  an  impulse 
can  reach  and  excite  large  numbers  of  motor  cells  that  are  ordi- 
narily beyond  its  influence  (general  spinal  convulsions). 

Peripheral  Nerves. — There  is  no  effect  in  man.  In  the  frog 
large  quantities  may  depress  the  ends  of  the  vagus  nerves  and  of 
the  sensory  and  motor  nerves ;  and  in  animals  in  which  strychnine 
convulsions  have  been  prevented  by  spinal  analgesia,  a  curare- 
like  effect  on  motor  nerve-endings  has  been  suspected. 

Comparison  of  Strychnine  and  Caffeine. — In  their  action  upon 
the  central  nervous  system  caffeine  and  strychnine  are  stimu- 
lants of  the  same  class.  But  caffeine  affects  the  cerebrum  most, 
while  strychnine  acts  most  upon  the  spinal  cord.  Both  stimu- 
late the  medullary  centers  more  or  less.  Pilcher  and  Sollmann 
state  that  from  doses  large  enough  to  be  dangerous  strychnine  is 
"usually  without  action  on  the  vasomotor  center,  but  occasion- 
ally may  stimulate  the  center  moderately." 

Muscle. — No  direct  action,  though  improved  muscular  power 
results  from  increased  tone  and  heightened  reflex  activity. 

Circulation. — In  perfusion  of  the  isolated  heart,  only  high 
concentrations  of  strychnine  have  any  effect,  so  the  heart  muscle 
is  not  stimulated  by  any  dose  that  would  be  given  to  man.  In 
perfusing  an  isolated  viscus  or  limb  there  is  no  effect  upon  the 
arteries.  In  the  intact  mammal,  after  therapeutic  doses,  there 
may  be  a  slight  slowing  of  the  pulse  from  a  moderate  stimulation 
of  the  vagus  center,  and  a  slight  rise  of  arterial  pressure  from 
stimulation  of  the  vasoconstrictor  center,  but,  as  a  rule,  the 
effect  on  blood-pressure  is  very  slight,  if  any.  In  cases  of  general 
weakness  the  improvement  in  general  muscular  tone  may  have 
a  good  effect  upon  the  circulation,  but  it  is  a  mistaken  idea 
among  physicians  that  strychnine  is  a  direct  stimulant  to  the 
heart. 

To  test  strychnine  clinically,  Cook  and  Briggs  injected  «V 
to  TV  grain  (0.001-0.006  gm.j.  In  persons  ill  enough  to  be  in 
bed,  they  obtained  a  slow  rise  of  pressure  lasting  from  one  to 
four  hours.  There  was  no  effect  on  the  pressure  in  the  normal 
persons  or  in  patients  that  were  moribund.  Richard  C.  Cabot 
made  about  5000  observations  of  the  arterial  pressure  before 


276  PHARMACOLOGY   AND   THERAPEUTICS 

and  after  strychnine  in  50  fever  cases,  Including  31  of  typhoid 
and  4  of  pneumonia.  In  32  of  the  50  cases  the  drug  was  given 
by  mouth,  in  18  hypodermatically.  The  usual  daily  dosage 
totaled  I  grain  (0.08  gm.).  In  16  cases  there  was  a  rise  in  blood- 
pressure  of  5  mm.  or  more;  in  24  cases  no  change  in  blood- 
pressure,  and  in  17  cases  a  fall  of  pressure;  the  average  change 
in  blood-pressure  was  no  greater  than  in  that  of  the  controls 
(18  cases).  Newburgh  gave  i^  grain  (0.09  gm.)  in  three  days  to 
each  of  5  patients  without  any  effect  on  circulation  or  respiration, 
though  toxic  symptoms  appeared.  These  experiments  must  not 
be  too  convincing,  however,  for  we  have  evidence  in  man  that  the 
circulation  may  be  greatly  improved  without  the  arterial  pressure 
being  raised.  (See  Digitalis.)  Yet  they  are  in  line  with  the 
findings  of  the  experimental  laboratory. 

On  the  other  hand,  Marvin,  1913,  tested  10  healthy  students 
by  intramuscular  injection.  From  ^V  grain  (0.002  gm.)  he 
obtained  a  slowing  of  7  beats  and  a  rise  in  pressure  of  13  mm. 
(average).  The  pressure  returned  to  its  previous  level  in  forty 
to  sixty  minutes. 

During  a  convulsion  the  blood-pressure  is  very  high,  because 
of  the  great  general  muscular  contraction,  but  this  is  of  no  in- 
terest to  us  in  therapeutics.  The  skin  vessels,  especially  those  of 
the  face,  may  be  dilated  from  a  special  vasodilator  action. 

Blood. — In  the  Journal  of  Infectious  Diseases,  1913,  Arkin 
gives  evidence  that  strychnine  has  a  marked  stimulating  action 
on  the  phagocytosis  of  streptococci  by  human  leukocytes  in  the 
presence  of  human  serum. 

Respiratory. — Large  therapeutic  doses  scarcely  affect  respira- 
tion. Parkinson  and  Rowlands  and  Edsall  and  Means  obtained 
no  effect  from  73-  grain  (0.004  gm-)>  and  Newburgh  no  effect  from 
ii40  grains  (0.09  gm.)  in  three  days  in  each  of  5  patients.  It  is 
possible  that  strychnine  increases  the  sensitiveness  of  the  center 
to  other  drugs.  Large  poisonous  doses  overwhelm  and  quickly 
exhaust  the  center.  Death  takes  place  from  asphyxia,  due  either 
to  the  setting  of  the  respiratory  muscles  during  a  convulsion,  or 
to  exhaustion  of  the  respiratory  center  (between  the  convulsions). 

Under  therapeutic  doses,  the  bronchial  muscles  are  improved 
in  tone,  so  the  drug  may  be  useful  in  relaxed  conditions  of  the 
bronchi;  while  in  spasmodic  conditions,  as  in  bronchial  asthma, 
it  will  be  harmful. 

In  cough  the  reflex  excitability  is  increased,  so  that  when 
there  is  abundant  secretion  to  be  coughed  up,  strychnine  may 
change  a  weak,  ineffective  cough  into  an  effective  one.  But 
when  the  cough  is  from  a  dry  or  tickling  throat  and  cannot  be 
made  effective  in  getting  rid  of  the  offending  stimulus,  strych- 


NUX    VOMICA  277 

nine  only  uselessly    increases    the    cough    and    distresses    the 
patient. 

Metabolism. — Because  of  the  heightened  muscular  tone  there 
is  some  increased  metabolism,  as  shown  by  increased  absorption 
of  oxygen  and  increased  output  of  carbon  dioxide.  In  convul- 
sions the  metabolism  is  greatly  increased. 

Temperature. — There  is  greater  production  of  heat,  owing  to 
the  increased  metabolism,  and  greater  dissipation  of  heat  from 
the  dilatation  of  the  cutaneous  vessels;  the  net  change  is  not 
enough  to  be  important.  During  a  convulsion  there  is  a  great 
production  of  heat. 

Excretion. — Some  of  the  drug  is  oxidized  and  destroyed  quite 
rapidly  in  the  tissues;  the  remainder  is  eliminated  in  the  urine. 
It  can  be  detected  in  the  urine  very  soon  after  the  dose  is  ad- 
ministered, and  most  of  it  is  excreted  within  twelve  hours,  but 
traces  may  be  present  for  four  or  five  days.  From  maximum 
doses  cumulative  poisoning  may  occur,  though  this  is  infrequent. 
In  strychnine  poisoning  the  urine,  concentrated  by  boiling  and 
injected  into  a  frog,  may  give  the  characteristic  convulsions. 

Tolerance. — Hare  has  given  some  evidence  that  there  is  no 
tolerance  for  strychnine  (Amer.  Jour.  Physiol.,  v).  Worth  Hale 
produced  it  with  difficulty  in  dogs,  but  more  readily  in  guinea- 
pigs.  In  human  beings,  if  the  dose  is  increased  very  slowly,  a 
certain  amount  of  tolerance  may  be  set  up.  For  example,  if  a 
patient  is  started  on  -£$  grain  (0.002  gm.)  three  times  a  day,  the 
dose  may  be  slowly  and  steadily  increased  until  in  five  or  six 
weeks  the  patient  is  getting  |  or  ^  grain  (o.oi  or  0.012  gm.) 
three  times  a  day  with  no  untoward  symptoms,  though  such 
dosage  would  have  been  poisonous  in  the  beginning.  In  loco- 
motor  ataxia,  progressive  muscular  atrophy,  optic  nerve  atrophy, 
etc.,  Troisfontaines  has  reached  doses  of  fV  to  TG5  grain  (0.018- 
0.035  Sm-)  daily,  and  Graeme  Hammond  has  been  able  to  in- 
crease the  daily  dosage  to  f  or  |  grain  (0.04-0.05  gm.),  without 
untoward  effects.  Other  neurologists  have  had  similar  experi- 
ence in  producing  tolerance  to  these  large  doses. 

Toxicology. — After  the  repeated  administration  of  large  doses 
of  strychnine  the  patient  may  become  restless  and  nervous  and 
twitchy,  may  make  abrupt  movements,  as  shrugging  one  shoulder 
or  twitching  the  fingers  or  an  arm  or  a  leg,  and  may  feel  a  stiff- 
ness of  the  face  muscles,  especially  when  he  laughs,  or  a  stiffness 
in  the  gait.  These  are  the  first  signs  of  strychnine  poisoning, 
and  the  drug  should  at  once  be  stopped.  If  considered  neces- 
sary, spinal  sedatives,  such  as  bromides,  may  be  administered. 

In  a  more  marked  stage  of  poisoning  the  twitches  become 
spasms,  and  soon  there  are  general  convulsions  of  the  spinal 


278  PHARMACOLOGY   AND   THERAPEUTICS 

type.  During  a  convulsion  all  the  voluntary  muscles  are  affected, 
so  of  two  opposing  sets  of  muscles  the  action  of  the  stronger 
set  predominates.  The  extensors  are  mostly  the  stronger, 
hence  the  arms,  legs,  and  back  are  extended  and  the  head  is 
thrown  back;  in  addition,  the  hands  may  be  clinched  and  the 
eyes  wide  open,  and  there  is  a  ghastly  grin,  the  risus  sardonicus, 
produced  by  the  spasmodic  drawing  out  of  the  corners  of  the 
mouth.  During  the  poisoning  the  mind  remains  clear,  conse- 
quently there  is  great  anxiety  on  the  part  of  the  patient;  and 
while  the  convulsions  last  there  is  great  muscular  pain  (cramps). 

The  convulsion  is  at  first  tonic,  that  is,  the  contraction  is 
continuous,  making  the  muscle  rigid;  it  then  changes  to  clonic, 
i.  e.,  rhythmic  intermittent  contraction;  then  it  ceases.  Before 
another  convulsion  sets  in  there  is  a  moment  of  great  muscular 
relaxation,  with  complete  prostration  and  soreness  of  the  muscles. 
If  the  poisoning  is  severe,  the  convulsions  follow  in  rapid  succes- 
sion, being  brought  on  by  the  slightest  stimulus — the  slamming  of 
a  door,  a  touch,  a  flash  of  light,  a  puff  of  air,  the  moving  of  a 
limb,  talking  or  any  voluntary  effort.  In  mammals,  after  a  few 
convulsions,  there  is  complete  exhaustion  with  collapse.  Death 
takes  place  from  asphyxia,  due  either  to  exhaustion  of  the  respira- 
tory center  or  to  continuous  spasm  of  the  respiratory  muscles.  The 
heart  may  keep  on  beating  for  some  time  after  respiration  has 
ceased.  It  is  put  under  great  strain  by  the  repeated  convulsions. 
Death  usually  takes  place  inside  of  two  hours. 

One-twelfth  grain  (0.005  gm.)  of  strychnine  sulphate  in  a 
woman  has  given  beginning  toxic  symptoms;  -5-  grain  (0.05  gm.) 
in  a  day  has  been  well  borne  by  patients  who  had  become  toler- 
ant to  the  drug.  Shoemaker  reports  recovery  in  three  hours  of 
a  student  who  had  taken  thirty  TV  grain  (0.004  gm-)  pills  of  the 
sulphate.  Hewlett  reports  restoration  in  a  man  after  15  grains 
(0.972  gm.).  He  recovered  over  if  grains  (o.u  gm.)  from  the 
urine  and  4.5  grains  (0.3  gm.)  from  the  first  stomach  washing. 
A  dose  of  T|(1  grain  (0.0004  gm-)  P^r  kilo  intravenously  or  intra- 
muscularly is  invariably  fatal  to  dogs  (Githens  and  Meltzer). 

Treatment. — If  the  drug  has  been  swallowed,  but  symptoms 
of  poisoning  have  not  yet  come  on,  the  stomach  should  be 
thoroughly  lavaged,  and  tannic  acid  or  even  tea  administered  to 
form  the  rather  insoluble  strychnine  tannate,  and  thus  retard 
absorption.  The  tannate  formed  must  be  washed  out  at  once, 
as  it  is  slowly  absorbed.  If  tea  is  employed,  immediate  lavage 
is  particularly  necessary,  lest  the  caffeine  of  the  tea  be  absorbed 
and  increase  the  poisonous  effect.  Most  of  the  caffeine  may 
be  got  rid  of  by  sleeping  the  tea  in  boiling  water  for  three 
minutes,  discarding  this  water,  and  then  steeping  the  residue  to 


NUX   VOMICA  279 

extract  the  tannic  acid  (Hatcher).  If  the  convulsions  have 
begun,  lavage  may  also  be  indicated;  but  usually,  because  of  the 
rapid  absorption  of  the  drug,  it  is  useless  at  this  stage.  Before  a 
stomach-tube  can  be  inserted  it  may  be  necessary  to  administer 
ether. 

The  systemic  treatment  consists  of— 

1.  Spinal  Cord  Sedatives. — For  quick  action,  chloroform  or 
ether  by  inhalation.     Ether  is  said  to  have  proved  an  effective 
antidote  in  dogs.     Hewlett  kept  his  patient  continuously  under 
ether  for  about  six  hours  and   so  abolished  the  convulsions. 
But  general  anesthesia  must  be  used  with  caution;  for  both 
chloroform  and  ether  tend  to  increase  the  already  serious  mus- 
cular relaxation  between  the  convulsions,  and  chloroform  de- 
presses the  respiratory  center.     Failure  of  this  center  in  strych- 
nine poisoning  threatens  at  any  moment.     For  prolonged  effect, 
bromides  in  large  dose,  ^  ounce  (15  gm.)  by  mouth  or  rectum. 
These  are  directly  antagonistic  to  strychnine  in  their  action  upon 
the  cord.     Paraldehyde  does  not  depress  the  respiratory  center, 
and  may  be  of  use  in  some  cases.     (Morphine  should  not  be 
employed,  for  it  not  only  depresses  the  respiratory  center,  but 
also  fails  to  antagonize  the  strychnine  effect  upon  the  cord. 
Chloral  hydrate  is  sometimes  used;  but  in  safe  amounts  has 
too  little  action  upon  the  cord,  and,  like  chloroform,  has  the 
disadvantage    of    being    very    depressing    to    the    respiratory 
center.) 

Spinal  anesthesia  with  cocaine  has  been  effective  in  protect- 
ing the  trunk  and  hind-limbs  of  animals  from  the  convulsions, 
but  it  does  not  protect  the  fore-limbs  and  head,  and  does  not 
prevent  the  great  relaxation  of  the  voluntary  muscles,  even  in 
the  hind-limbs.  Magnesium  sulphate  intraspinally  or  intra- 
venously would  be  better. 

2.  Artificial  Respiration  and  the  Inhalation  of  Oxygen. — The 
oxygen  acts  not  only  to  furnish  respiratory  oxygen,  which  is 
deficient  because  of  the  interference  with  respiration  and   of 
muscular  activity,  but  also  to  increase  the  rapidity  of  oxidation 
of  the  strychnine  in  the  body.     Gies  and  Meltzer  claim  that  the 
rhythmic  motions  of  artificial  respiration  tend  to  delay  the  onset 
of  convulsions. 

j.  Cathetcrization  of  the  bladder  to  remove  and  so  prevent 
reabsorption  of  the  strychnine  passed  out  by  the  kidneys. 

4.  Saline  Infusion. — Delbert  found  that  if  he  followed  the 
injection  of  a  lethal  dose  of  strychnine  into  a  dog  by  an  intrave- 
nous infusion  of  normal  saline,  free  diuresis  promptly  resulted  and 
no  signs  of  strychnine  poisoning  were  manifest.  Hatcher  and 
Smith  found  that  diuresis  hastened  the  elimination  of  the  drug, 


280  PHARMACOLOGY   AND    THERAPEUTICS 

but  never  sufficiently  to  save  an  animal  given  20  per  cent, 
above  the  average  lethal  dose.  Githens  and  Meltzer  (1912) 
recommend  the  combination  of  ether  anesthesia,  intratracheal 
insufflation,  and  intravenous  administration  of  Ringer's  solu- 
tion. 

Therapeutics. — Strychnine  and  nux  vomica  preparations 
are  extensively  employed  as  tonics  in  conditions  of  debility  with 
loss  of  appetite,  and  in  convalescence  from  severe  illnesses.  In 
these  conditions  the  effect  on  appetite  is  of  value  as  well  as  that 
on  tone.  For  a  more  marked  action  on  the  reflexes,  they  are 
given  in  atonic  conditions  of  the  abdominal  viscera,  as  of  stomach, 
intestines,  bladder,  and  uterus,  in  the  relaxed  atonic  types  of 
chronic  bronchitis,  in  conditions  of  weak,  ineffective  cough, 
as  in  severe  tuberculosis  with  much  bronchial  secretion,  and  in 
acute  and  chronic  alcoholism.  "Strychnine  is  to  asthenia  what 
morphine  is  to  pain"  (Hartenberg) . 

Further,  in  serious  acute  diseases  like  pneumonia,  where 
there  is  much  prostration,  and  in  narcotic  poisoning,  as  from  alco- 
hol, ether,  or  chloral  hydrate,  large  doses  may  be  administered 
for  respiratory  and  spinal  stimulation.  It  is  to  be  noted  that 
while  strychnine  is  good  in  chloral  poisoning,  chloral  hydrate  is 
not  good  in  strychnine  poisoning. 

In  nervous  disease  strychnine  is  extensively  employed,  but 
its  use  requires  careful  discrimination.  Its  application  is  as 
follows : 

(a)  In  the  postoperative  paralysis  of  stomach  or  intestine 
the  drug  would  seem  to  be  the  best  that  we  have. 

(ft)  In  paralysis  from  disease  of  the  anterior  horn  cells  (an- 
terior poliomyelitis,  progressive  muscular  atrophy,  amyotrophic 
lateral  sclerosis)  moderate  improvement  may  come  from  in- 
creased transmission  of  the  regular  afferent  impulses. 

(c)  In  lesions  involving  the  posterior  columns  of  the  cord 
(e.  #.,  locomotor  ataxia)  the  result  is  problematic.    Large  doses 
may  bring  about  improvement  in  some  of  the  functions,  but 
often  are  of  no  value  at  all. 

(d)  In  sexual  feebleness  without  evidence  of  an  organic  lesion 
the  effect  on  the  reflexes  may  be  of  value. 

(c]  In  paralysis  due  to  lesions  of  the  motor  area  of  the  brain, 
or  of  the  motor  tract  of  brain  or  cord,  the  tendency  of  the  drug 
is  harmful;  for  the  reflexes  of  the  cord  below  the  lesion  are  cut  off 
from  the  normal  cerebral  control.  As  a  result,  they  are  so  height- 
ened in  activity  that  they  approach  the  incoordinated  type.  The 
muscles  are  in  a  state  of  overtone,  and  in  voluntary  motion  the 
opposing  muscles  do  not  readily  relax;  so  it  requires  but  slight 
provocation  to  bring  the  limb  into  a  state  of  spasticity  or  rigidity 


NUX   VOMICA  28l 

with  perhaps  clonic  contraction  of  the  muscles  (as  in  the  spastic 
gait).  Therefore  in  hemiplegia,  multiple  sclerosis,  transverse 
myelitis,  and  other  conditions  with  spastic  paralysis,  strychnine 
would  tend  to  increase  the  already  bad  condition.  The  writer 
found  a  man  with  multiple  sclerosis  who  was  being  given  two  pills 
of  aloin,  belladonna,  and  strychnine,  ^0  grain  (o.ooi  gm.)  in  each 
three  times  a  day,  together  with  strychnine  sulphate,  ^V  grain 
(0.002  gm.),  and  a  dose  of  Bright's  tonic,  containing  strychnine 
sulphate,  -%•$  grain  (o.ooi  gm.).  The  amount  of  strychnine 
sulphate  being  administered  was  thus  -^  grain  (0.005  gm.) 
three  times  a  day.  He  was  in  such  a  spastic  condition  that  he 
could  not  walk,  and  could  scarcely  use  his  hands  to  button  his 
clothes.  The  substitution  of  bromides  for  the  strychnine  re- 
sulted in  a  marked  improvement  in  two  days. 

(/ )  In  diminished  vision,  whether  functional  or  from  retinitis 
or  partial  optic  nerve  atrophy,  large  doses  sometimes  give  good 
results.  In  these  cases  the  drug  may  be  given  internally  in  the 
usual  way;  or,  if  the  eye  only  is  to  be  treated,  may  be  injected 
into  the  neighborhood  of  the  affected  eye,  or  even  in  i  per  cent, 
solution  dropped  into  the  eye. 

Contraindications. — Spasmodic  conditions  of  all  kinds,  as — (a) 
Of  smooth  muscle — spasmodic  asthma  and  biliary,  renal,  or  intes- 
tinal colic,  or  spastic  constipation;  (b)  of  voluntary  muscle — 
hiccup,  convulsive  tic,  epilepsy,  and  any  spastic  condition,  as 
from  a  lesion  involving  the  motor  area  or  tract.  Strychnine  or 
nux  vomica  should  not  be  given  if  the  reflexes  are  already  over- 
active. 

Administration. — For  a  bitter  effect,  the  tincture  of  nux 
vomica  is  preferred  (10  minims  =  y^  grain  of  strychnine,  or 
about  -g^  grain  of  strychnine  sulphate).  It  is  given  about 
ten  minutes  before  meals,  diluted  with  water  to  make  a  bitter 
drink.  For  the  purposes  of  a  bitter  it  is  useless  if  given  in  cap- 
sules or  coated  pills.  For  a  tonic  effect  any  of  the  preparations 
may  be  employed,  the  strychnine  salts  being  frequently  pre- 
scribed by  themselves  in  the  form  of  tablet  triturates.  For 
hypodermatic  use,  the  strychnine  salts  alone  are  suitable. 


As  camphor  has  already  been  considered,  and  the  other 
central  stimulants,  atropirie  and  cocaine,  are  at  the  same  time 
pronounced  peripheral  depressants,  we  shall  defer  their  consid- 
eration for  the  present. 


282  PHARMACOLOGY   AND   THERAPEUTICS 

REMEDIES  WHICH  DEPRESS  THE  CENTRAL  NERVOUS  SYSTEM 

—NARCOTICS 

As  the  remedies  which  depress  the  central  nervous  system 
regularly  depress  the  cerebrum,  they  are  known  generally  as 
narcotics,  a  narcotic  being  a  remedy  which  tends  to  produce  a 
depressed  state  of  consciousness.  Consciousness  is  a  function  of 
the  cerebral  cortex.  The  rapidity  of  the  onset  of  narcosis  varies 
greatly  with  the  different  narcotics,  but  the  degree  of  narcosis 
increases  in  a  regular  way  with  the  amount  given.  Slight 
narcosis,  for  example,  shows  merely  in  a  tendency  to  quietness, 
while  greater  degrees  show  in  succession  drowsiness  with  mental 
and  physical  sluggishness,  then  sleep,  not  quite  like  the  natural 
sleep,  then  stupor,  and  finally  loss  of  consciousness  (coma). 
Stupor,  or  torpor,  is  a  condition  of  unconsciousness  or  semicon- 
sciousness  from  which  one  can  be  aroused,  but  with  difficulty; 
and  coma,  a  condition  of  unconsciousness  from  which  one  cannot 
be  aroused. 

The  classes  of  narcotics  are:  (i)  General  Anesthetics;  (2) 
Intoxicants;  (3)  Hypnotics;  (4)  Antihysterics. 

Narcosis  Theories. — There  are  several  theories  as  to  the 
manner  in  which  narcotic  drugs  reach  the  cerebral  cell  contents, 
and  as  to  how  they  act  to  produce  anesthesia.  The  best  known 
are: 

1.  The  Meyer-Over  ton,  which  was  propounded  by  Meyer  and 
Overton  independently.     It  is  that  these  drugs  exert  their  main 
action  on  the  central  nervous  system,  because  they  are  taken 
up  by  the  fats  and  lipoids  which  abound  there,  and  so  are  held  in 
considerable  amount  in  contact  with  the  cell  structures.     The 
lipoids  are  lecithin,  cholesterin,  cerebrin,  protagon,  etc.     Accord- 
ing to  these  authors,  the  anesthetic  property  increases  with  the 
solubility  in  fats  and  lipoids  and  the  insolubility  in  water.     The 
relation  of  the  activity  of  hypnotics  and  anesthetics  to  their 
solubility  in  lipoids  is  certainly  a  striking  one,  and  there  is  a 
very  large  amount  of  evidence  supporting  this  theory,  which  is 
the  one  most  generally  accepted.     It,  of  course,  merely  indicates 
how  the  anesthetic  gets  to  the  nerve-cell,  and  not  what  takes  place 
in  the  cell. 

2.  The  Theory  of  Moore  and  Roaf. — They  believe  that  nar- 
cosis or  anesthesia  is  due  to  a  change  in  the  protoplasm  of  the 
cerebral   cells  by   the   formation   of-  loose   compounds  of  ether, 
chloroform,  etc.,  with  the  cell  proteins,  and  that  this  results  in 
limitation   of   the    activities   of   the   cerebral   protoplasm.     On 
account  of  the  instability  of  the  compounds,  these  remain  formed 
only  so  long  as  the  vapor-pressure  of  the  anesthetic  in  the  blood 
is  maintained;  so  on  stopping  the  administration  of  the  anes- 


NARCOTICS  283 

the  tic  the  narcosis  soon  ceases.  In  the  words  of  Moore  and 
Roaf,  "that  a  certain  amount  of  the  anesthetic  will  be  taken  up 
by  the  lipoid  in  a  physical  fashion  there  can  be  no  doubt,  because 
of  the  high  solubility  of  these  anesthetics  in  such  lipoid  substances. 
But  we  hold  that  the  portion  of  the  anesthetic  so  taken  up  and 
held  by  the  lipoid  is  passive  and  not  active,  and  that  it  is  the 
portion  taken  up  by  the  protein  which  is  active  in  paralyzing 
protoplasmic  activity  and  producing  anesthesia.  It  is  a  matter 
of  common  knowledge  that  the  greater  the  amount  of  fatty 
tissue  in  a  subject  undergoing  anesthetization,  the  greater  is 
the  amount  of  anesthetic  required.  The  portion  of  anesthetic 
absorbed  by  the  lipoid  is  imprisoned,  and  more  anesthetic  must 
be  given  in  order  to  raise  the  (vapor)  pressure  of  the  anesthetic 
sufficiently  to  cause  combination  between  cell  protoplasm  and 
anesthetic,  with  resulting  anesthetization." 

The  one  theory  assumes  that  the  ether  dissolved  in  the  fats 
and  lipoids  is  the  anesthetic  ether;  the  other  considers  this  ether 
lost  or  imprisoned,  and  the  anesthetic  ether  to  be  only  that  which 
enters  into  combination  with  the  cell  proteins. 

3.  That  of  Verworn. — He  accepts  the  Meyer-Overton  theory 
as  showing  the  properties  necessary  for  an  anesthetic  to  reach 
the  field  of  action.  But  he  goes  on  to  give  an  explanation  of  the 
cause  of  the  depression  of  the  activity  of  the  cerebral  cells.  He 
shows  that  in  narcosis  there  is  interference  with  the  oxidative 
processes  of  the  cells,  or,  in  his  own  words,  "the  factor  which 
produces  the  characteristic  symptom-complex  of  narcosis  is 
under  all  circumstances  the  suppression  of  the  power  to  carry  on 
oxidations."  His  theory  is  that  narcotics  render  the  oxidases 
(the  oxygen  carriers)  in  living  tissues  incapable  of  carrying 
oxygen.  He  shows  that  this  may  take  place  in  any  cells  of  the 
body,  but  that  the  cells  of  the  cerebral  cortex  are  especially  sen- 
sitive to  lack  of  oxygen,  and  are  depressed  with  very  much  less  of 
the  narcotic  than  is  necessary  to  depress  the  nerves  and  muscles. 

One  of  his  experiments  may  be  cited:  The  sciatic  nerve  of  a 
frog  was  deprived  of  oxygen  until  its  irritability  was  much  reduced 
and  its  conductivity  lost.  It  was  then  narcotized  with  ether. 
During  the  ether,  oxygen  was  supplied  for  a  long  time,  but  it  had 
no  effect  whatever  upon  the  narcosis.  Then  nitrogen  was  sub- 
stituted for  the  oxygen,  and  the  narcotic  was  stopped.  Still, 
though  the  ether  passed  off,  the  functions  were  not  restored  in 
the  nitrogen  atmosphere.  After  a  while  the  nitrogen  was  re- 
placed by  air,  and  in  one  minute  the  nerve  had  recovered  its 
conductivity  and  its  irritability.  That  is,  so  long  as  the  cell  was 
under  the  narcotic  influence,  oxygen  had  no  power  to  set  the  cell 
functionating,  but  did  set  it  functionatino;  when  the  narcotic  had 


284  PHARMACOLOGY   AND   THERAPEUTICS 

been  removed.  Also  the  mere  removal  of  the  narcotic  was  not 
enough,  but  oxygen  was  necessary  to  restore  the  lost  functions 
of  the  cell. 

In  opposition  to  this  theory  is  the  demonstration  by  Winter- 
stein  that  intestinal  parasites  keep  alive  and  active  in  unoxygen- 
ated  fluids,  yet  respond  by  narcosis  to  alcohol  and  chloroform; 
and  the  demonstration  by  Loeb  and  Wastenys  that  in  certain 
low  forms  profound  narcosis  can  be  induced  without  any  note- 
worthy diminution  of  the  normal  rate  of  oxidation,  and  that  in 
order  to  depress  oxidation  a  narcotic  must  be  given  in  far  greater 
concentration  than  is  required  for  narcosis. 

General  Anesthetics 

The  ones  in  common  use  are:  Ether,  chloroform,  nitrous  oxide, 
ethyl  chloride,  and  magnesium  sulphate. 

As  ether  and  chloroform  have  uses  in  therapeutics  which  do 
not  involve  the  production  of  general  anesthesia,  we  shall  first 
take  up  their  general  pharmacology  and  therapeutics,  and  after- 
ward their  special  uses  as  anesthetics. 

ETHER 

Ether,  or  ethyl  oxide,  (C2H5)2O,  is  obtained  by  distilling  a 
mixture  of  sulphuric  acid  and  alcohol.  It  is  a  very  volatile, 
light,  colorless,  limpid  liquid,  with  a  burning,  unpleasant  taste 
and  a  characteristic  penetrating  odor.  It  boils  at  about  35.5°  C. 
(96°  F.),  and  should,  therefore,  boil  when  a  test-tube  of  it  con- 
taining some  broken  glass  is  held  for  a  time  closely  grasped  in  the 
hand.  It  is  highly  inflammable,  and  its  vapor  mixed  with  air  is 
explosive.  It  mixes  freely  with  alcohol  and  chloroform,  and  is  a 
solvent  of  resins,  fats,  oils,  adhesive  plaster,  and  collodion.  It 
is  soluble  up  to  about  8  per  cent,  in  water  and  u  per  cent,  in 
blood-serum.  Its  chief  impurities  are  acids,  acetaldehyd,  and 
peroxides.  Even  in  originally  pure  specimens  these  impurities 
may  develop  in  the  presence  of  light  and  air.  They  are  removed 
if  the  vapor  is  passed  through  water. 
Preparations  and  Doses. — 

Ether  (aether),  by  mouth,  15  minims  (i  c.c.). 
Spirit,  32.5  per  cent.,  i  dram  (4  c.c.). 
The  long-used  remedy,  Hoffmann's  anodyne  (compound 
spirit  of  clhcr,  consisting  of  ether,  32.5  per  cent.,  and 
ethereal  oil,  2.5  per  cent.),  i  dram  (4  c.c.),  is  no  longer 
pharmacopceial.     It  has  a  sharp,  unpleasant  taste,  but 
is  the  favorite  preparation  for  stomach  administration. 


ETHER  285 

Pharmacologic  Action. — Ether  is  a  general  protoplasmic 
poison. 

Microorganisms. — It  is  disinfectant.  W.  H.  Park  found  that 
a  mixture  of  3  parts  of  ether  and  one  part  of  olive  oil  would  kill 
colon  bacilli  in  one  minute. 

Skin,  Mucous  Membranes,  and  Peritoneum. — If  applied  to  the 
skin  and  allowed  to  evaporate,  ether  blanches  and  cools  the  part 
by  its  rapid  evaporation;  if  it  is  applied  in  the  form  of  a  fine 
spray,  it  evaporates  so  rapidly  that  the  part  is  numbed  by  the 
cold  or  may  even  be  frozen.  If  applied  to  the  skin  and  not  allowed 
to  evaporate,  it  irritates  and  is  rubefacient.  To  mucous  mem- 
branes it  is  very  irritant,  so  for  administration  by  stomach  it 
requires  dilution  with  water,  and  for  administration  by  the  lungs 
it  requires  dilution  with  air  or  oxygen.  To  the  peritoneum  it  is 
not  irritant. 

Alimentary  Tract. — It  has  a  burning,  unpleasant  taste,  irri- 
tates the  mouth,  and  induces  a  reflex  flow  of  saliva  and  mucus. 

In  the  stomach,  if  given  undiluted,  it  burns  and  may  induce 
vomiting.  If  moderately  diluted,  it  is  carminative,  tending  to 
promote  the  expulsion  of  gas  and  to  relieve  with  great  promptness 
the  reflex  and  direct  effects  of  a  distended  stomach  upon  the  heart, 
the  diaphragm,  and  the  abdominal  contents.  It  also  over- 
comes colic.  As  it  is  so  volatile,  it  is  very  prompt  in  its  action, 
but  it  may  produce  eructations  of  ether-tasting  gas,  especially  in 
fever  or  if  given  with  hot  water. 

Absorption  is  very  rapid,  whether  the  administration  is  by 
stomach  or  rectum  or  lungs. 

Circulation. — From  local  irritation,  whether  from  inhalation, 
swallowing,  or  hypodermic  injection,  there  is  a  prompt  but  mo- 
mentary reflex  stimulation  of  the  heart's  rate  and  force  with  rise 
in  arterial  pressure.  This  is  due  probably  to  reflex  stimulation 
of  the  accelerator  center  and  reflex  stimulation  of  the  vasocon- 
strictor center.  It  is  a  slight  effect  at  best,  and  is  proportional 
to  the  degree  of  local  irritation  produced. 

Muehlberg  and  Kramer  have  shown  that  the  injection  of  a 
few  minims  of  undiluted  ether  into  the  carotid  artery  of  a  rabbit, 
so  that  it  passes  at  once  to  the  medullary  centers,  is  followed 
immediately  by  intense  stimulation  of  the  vagus  and  vasocon- 
strictor centers.  Thus  it  causes  vagus  weakening  of  the  heart, 
and  at  the  same  time  excessive  peripheral  resistance.  The 
result  is  stoppage  of  the  heart  in  a  condition  of  dilatation.  In 
laboratory  animals  death  in  this  manner  frequently  results  if  an 
overwhelming  amount  of  ether  is  administered  at  the  outset.  In 
man  no  such  deaths  are  reported,  and  this  may  be  because 
ether  is  so  irritant  that  it  needs  to  be  administered  gradually. 


286  PHARMACOLOGY  AND  THERAPEUTICS 

For  it  is  found  that  if  the  administration  is  gradual,  whether  by 
inhalation,  by  rectum,  or  by  vein,  the  centers  become  narcotized 
so  that  they  are  resistant  to  the  irritant  effect.  In  careful  anes- 
thesia the  effect  upon  the  medullary  centers  is  very  little  if  any 
at  first,  but  after  a  time  they  become  depressed. 

The  heart  muscle  may  be  temporarily  stimulated,  as  it  tends 
to  be  by  protoplasmic  irritants,  but  after  a  time,  in  prolonged 
anesthesia,  or  if  overwhelming  amounts  of  ether  are  given,  it 
shows  weakening.  Loeb  found  that  when  the  perfusing  fluid 
contained  0.4  per  cent,  of  ether,  an  isolated  dog's  heart  stopped 
in  extreme  diastolic  relaxation. 

With  amounts  such  as  are  used  in  the  average  anesthesia 
there  may  be  a  rise  in  blood-pressure  for  the  first  fifteen  minutes, 
and  then  a  slight  lowering  to  the  normal  or  slightly  below  normal. 
The  rate  is  somewhat  increased,  and  there  is  marked  flushing  of 
the  skin  from  dilatation  of  the  cutaneous  arterioles. 

Blood. — As  administered  to  man,  ether  does  not  reach 
a  concentration  to  interfere  with  the  oxygen-carrying  power 
of  the  blood.  Viscosity  and  coagulation  are  scarcely  affected, 
if  at  all.  Mann  says  that  the  number  and  fragility  of  red  blood- 
cells  and  the  amount  of  hemoglobin  are  unchanged,  but  the 
number  of  leukocytes  is  regularly  increased. 

Respiration. — The  reflex  stimulation  from  mouth,  stomach, 
or  respiratory  passages  extends  to  the  respiratory  center,  and 
breathing  is  at  first  quickened  and  deepened.  Henderson 
thinks  that  this,  with  the  resistance  in  the  first  stages  of  anes- 
thesia, is  a  possible  cause  of  acapnia.  After  absorption,  ordinary 
amounts  have  little  effect;  but  large  amounts,  as  in  anesthesia, 
tend  to  depress  the  center.  The  usual  cause  of  death  is  asphyxia 
from  respiratory  paralysis.  In  experiments  with  very  dilute 
ether  the  respiration  regularly  fails  before  the  heart,  though 
the  latter  is  very  weak  and  interferes  with  restitution. 

Nervous  System. — Like  other  strong  carminatives,  ether 
tends  to  overcome  hysteric  conditions  and  states  of  nervous 
instability.  It  probably  acts  reflexly  from  the  stomach  as  a 
cerebral  stimulant,  promoting  the  control  of  the  highest  cen- 
ters. 

After  absorption  it  acts  as  a  direct  cerebral  depressant  or 
sedative,  depressing  the  intellectual  centers  and  the  motor  areas. 
Hence  small  amounts  may  be  hypnotic,  and  large  amounts  will 
induce  coma,  as  in  anesthesia. 

For  the  nervous  structures  themselves  it  has  a  special  affinity, 
and  after  an  ether  death  more  ether  is  found  in  the  brain  than  in 
any  other  organ.  There  are  several  theories  to  account  for  this 
accumulation  in  the  central  nervous  system,  and  the  production 


ETHER  287 

of  narcosis  by  ether,  chloroform,  and  similar  substances.  We 
shall  speak  of  them  later. 

In  poisoning  by  ether  there  is  a  progressive  depression  of  the 
central  nervous  system.  The  higher  cerebral  functions,  those 
involving  intellectual  processes,  as  self-control,  judgment,  and 
reason,  are  the  first  to  succumb,  so  that  the  emotions  are  freed 
from  control.  Then  the  emotions,  the  perceptions,  the  motor 
functions,  and  coordination  by  the  cerebellum  are  depressed. 
Then  there  is  abolition  of  the  spinal  reflexes,  and  finally  depres- 
sion of  the  vital  medullary  centers.  Sensory  centers  are  affected 
before  motor,  so  complete  insensitiveness  to  the  surroundings 
and  to  pain,  i.  e.,  complete  abolition  of  the  perceptions,  precedes 
complete  muscular  relaxation.  The  action  of  ether  upon  the 
brain  and  spinal  cord  is  directly  antagonistic  to  that  of  caffeine 
and  strychnine.  The  sensory  nerve-endings  are  also  somewhat 
depressed. 

Eye. — As  affected  in  the  production  of  anesthesia,  the  pupil 
is  at  first  dilated  reflexly,  either  from  excitement,  from  irritation 
of  the  nose  and  throat,  or  from  pain.  It  has  the  usual  sensi- 
tiveness to  light.  In  the  stage  of  stupor  it  contracts  as  in  sleep 
and  is  still  quite  sensitive  to  light.  In  the  stage  of  complete 
anesthesia  it  is  in  mid-dilatation  (Hewitt  says  3.5  to  4.5  mm.  in 
diameter)  and  almost  insensitive  to  light.  This  is  due  to  depres- 
sion of  the  third  nerve  center,  which  in  the  light  reflex  controls 
the  constrictor  muscle  of  the  iris.  In  the  stage  of  collapse  the 
pupil  is  dilated  and  insensitive  to  light,  owing  to  the  paralysis  of 
this  center. 

Muscle. — In  perfusion  of  a  limb  there  is  no  weakening  of  the 
muscle  unless  the  ether  concentration  is  high. 

Temperature. — From  large  doses  the  temperature  tends  to 
fall,  both  because  of  a  striking  diminution  in  the  production  of 
heat  on  account  of  the  diminished  muscular  activity  and  loss  of 
tone,  and  of  increased  dissipation  of  heat  through  wide  dilatation 
of  the  cutaneous  vessels  and  sweating.  The  fall  in  temperature 
will  be  increased  by  exposure  during  an  operation. 

Elimination  is  rapid  and  essentially  by  the  lungs;  it  is  prob- 
able that  in  prolonged  anesthesia  some  passes  out  in  the  urine. 

Kidneys. — During  anesthesia  there  is  inhibition  of  urine 
formation,  owing  to  contraction  of  the  arterioles;  after  the  anes- 
thesia there  is  diuresis  (Hawk).  After  anesthesia  the  excretion 
of  phenolsulphonephthalein  is  often  considerably  retarded  and 
there  may  be  other  evidences  of  kidney  retention,  notably 
hyperglycemia  without  glycosuria.  Rarely  there  is  glycosuria, 
Albuminuria  is  frequently  noticed,  perhaps  in  one-fourth  of  the 
cases,  the  statistics  in  published  reports  varying  from  5  to  36  per 


PHARMACOLOGY   AND   THERAPEUTICS 

cent.  The  condition  is  usually  transitory,  but  occasionally  it 
goes  on  to  an  acute  nephritis,  with  albumin  and  blood  in  the  urine. 
This  would  seem  to  indicate  direct  irritation  of  the  kidney  cells  by 
the  ether,  but  it  is  a  result  that  may  be  due  to  the  local  contraction 
of  the  renal  vessels,  to  partial  asphyxia,  or  to  acidosis.  Acetone 
is  also  frequently  found  in  the  urine  for  one  or  two  days  after 
the  anesthesia. 

Skin. — From  moderate  doses  there  are  flushing  of  face  and 
neck  and  a  tendency  to  sweating.  From  anesthetic  amounts 
there  is  usually  flushing  of  the  whole  skin  with  profuse  sweating; 
and  sometimes  mottling  of  the  skin  or  a  general  erythema  of 
transitory  nature — the  so-called  "ether  rash." 

The  ether  habit  is  sometimes  encountered,  the  devotee  inhal- 
ing frequently  through  the  nostrils  or  swallowing  the  diluted 
drug. 

Therapeutics  of  ether  when  not  employed  as  a  general 
anesthetic.  Externally  and  Locally. — It  is  used  to  cleanse  the 
skin  preparatory  to  operations,  small  or  large.  It  has  been  em- 
ployed for  peritoneal  lavage  in  tuberculous  and  purulent  perito- 
nitis. (It  does  not  irritate  the  peritoneum.) 

Internally. — It  is  employed  in  the  form  of  Hoffmann's 
anodyne.  Though  the  taste  is  rank  and  unpleasant,  this  is  one 
of  our  most  powerful  carminatives.  On  account  of  the  volatility, 
eructations  may  keep  bringing  this  taste  back  into  the  mouth. 

The  therapeutic  uses  of  Hoffmann's  anodyne  are: 

1.  As  carminative  and  reflex  stimulant — in  flatulence,  and  espe- 
cially in  faintness  or  fainting  following  distention  of  the  stomach. 

2.  To  relieve  angina  pectoris  and  allied  cardiac  disturbances. 
It  acts  by  relieving  stomach  distention  and  by  its  reflex  effect 
upon  the  circulation. 

j.  To  relieve  dyspnea  (bronchial,  cardiac,  or  that  due  to  a 
much-distended  stomach) . 

4.  To  relieve  spasm — as  in  intestinal  colic,  spasmodic  asthma, 
and  hiccup. 

5.  To  allay  hysteria  and  states  of  nervous  instability. 
Because  of  the  bad   taste  and  eructations  it  is  sometimes 

mixed  with  ichthyol  and  the  tinctures  of  valerian  and  asafetida 
to  form  the  "bum  mixture,"  a  preparation  which  is  given  to 
hospital  bums  when  they  come  in  on  various  pretexts  of  illness 
merely  to  get  a  bed  and  meals.  The  repeated  gas  eructations 
caused  by  the  ether  keep  the  taste  of  this  mixture  in  the  mouth, 
and  the  result  is  the  willing  departure  of  the  patient  from  the 
hospital. 


Aur. 


B.P.I 


Fig.  38.- — Chloroform,  10  breaths,  (/>)  diminished  the  contractility  of  both 
auricle  and  ventricle,  and  caused  a  fall  in  blood-pressure  from  76  to  56  mm.  Caf- 
feine, 5  mg.  per  kilo,  (a)  resulted  in  increased  contractility  of  auricle  and  ventricle 
(down-stroke),  and  a  rise  in  blood-pressure  from  68  to  82  mm.  The  effect  was 
somewhat  lasting.  (Tracing  made  by  Dr.  C.  C.  Lieb.) 


CHLOROFORM  289 

CHLOROFORM 

Chloroform  (chlorof ormum) ,  CHCla,  is  a  non-inflammable, 
volatile  liquid,  which  is  about  i^  times  as  heavy  as  water, 
boils  at  141°  F.,  and  has  a  burning,  strikingly  sweetish  taste. 
It  mixes  freely  with  alcohol,  ether,  and  the  oils,  and  dissolves  to 
the  extent  of  about  0.5  per  cent,  in  water  (U.  S.  P.).  Moore  and 
Roaf  found  it  to  be  soluble  to  the  extent  of  0.95  per  cent,  in  water, 
and  to  the  extent  of  4  per  cent,  in  blood-serum,  and  their  work 
indicated  that  this  extra  solubility  in  serum  was  due  to  the  forma- 
tion of  a  loose  protein  compound. 

On  long  standing,  or  if  exposed  to  sunlight  or  a  flame,  chloro- 
form may  decompose,  with  the  formation  of  free  hydrochloric 
acid,  or  the  poisonous  carbonyl  chloride  (COC12),  or  free  chlorine, 
which  is  very  irritating.  Alcohol  acts  as  a  preservative,  as  the 
chloroform  does  not  undergo  decomposition  so  long  as  there  is 
any  alcohol  present  to  be  oxidized.  Hence  the  Pharmacopoeia 
specifies  that  0.6-1  per  cent,  of  alcohol  shall  be  present. 

Preparations  and  Doses. — 

Chloroform,  5  minims  (0.3  c.c.). 
Water  (|  per  cent.),  4  drams  (15  c.c.). 
Spirit  (6  per  cent.),  30  minims  (2  c.c.). 
Liniment — (chloroform,  30  per  cent.,  soap  liniment,  70  per 
cent.). 

Pharmacologic  Action. — Chloroform  is  a  general  proto- 
plasmic poison  of  considerable  destructive  power.  If  concen- 
trated, it  will  cause  the  death  of  tissues  with  which  it  comes  in 
contact;  and  even  when  dilute,  as  in  the  blood,  it  can  readily 
produce  degenerative  changes  in  various  organs  of  the  body. 
This  striking  property  seems  to  be  common  to  various  hydro- 
carbons which  contain  chlorine. 

Microorganisms. — Chloroform  is  antiseptic,  and  even  in  such 
a  dilute  solution  as  "chloroform  water"  (|  per  cent,  in  strength) 
will  retard  putrefaction  and  fermentation,  as  in  urine. 

Local. — It  is  less  volatile  than  ether,  so  is  less  cooling  to  the 
skin,  and  its  tendency  is  rather  to  irritate  than  to  soothe.  If  it 
is  dropped  on  the  face  from  a  chloroform  inhaler  and  prevented 
from  ready  evaporation,  it  will  make  a  decided  burn.  In  lini- 
ments, if  evaporation  is  prevented  by  covering  with  flannel  or 
oiled  silk,  it  is  counterirritant. 

Alimentary  Tract. — Undiluted,  it  is  very  irritating  to  throat 
and  stomach;  but  its  official  preparations,  being  very  dilute,  are 
sweet  to  the  taste  and  pleasant  carminatives.  They  are  also 
soothing  to  the  stomach  and  antemetic.  It  is  said  that  the 
activity  of  rennet  and  pepsin  is  promoted  by  solutions  of  less  than 
0.5  per  cent,  strength,  and  retarded  by  strong  solutions. 

19 


2 go  PHARMACOLOGY   AND   THERAPEUTICS 

Heart. — In  perfusing  an  isolated  heart,  the  addition  of  a 
small  amount  of  chloroform  results  in  a  momentary  strengthen- 
ing, followed  very  quickly  by  muscular  weakness,  the  heart  soon 
becoming  dilated  and  the  beats  small  and  ineffective.  The  drug 
is  a  strong  poison  to  cardiac  muscle.  Sherrington  and  Sowton 
found  that  in  a  perfusion  fluid  a  strength  of  0.05  per  cent,  of 
chloroform  was  sufficient  regularly  to  arrest  the  heart,  but  that 
restoration  would  take  place  on  returning  to  pure  saline.  That 
is,  when  the  osmotic  pressure  of  chloroform  in  the  cardiac  cells  is 
below  a  certain  limit,  the  heart  beats  again.  If  too  strong 
chloroform  is  used,  the  heart  cannot  dissociate  itself  from  the 
chloroform  and  death  ensues. 

Levy  and  Lewis,  experimenting  with  cats,  found  that  light 
anesthesia,  i.  e.,  with  the  tension  of  chloroform  vapor  in  the 
inspired  air  between  0.5  and  1.5  per  cent.,  regularly  produced 
irregularities  in  the  action  of  the  ventricle,  of  the  types  described 
under  "Digitalis"  as  due  to  excessive  irritability.  They  observed 
paroxysmal  tachycardia  (of  ventricular  origin),  premature  ven- 
tricular contractions,  and  ventricular  fibrillation.  The  increase 
of  the  vapor  tension  to  2  per  cent,  was  regularly  followed  by  the 
disappearance  of  the  irregularity.  Levy  considers  this  due  to 
muscle  weakening  and  dilatation  which  he  considers  protective 
against  fibrillation.  With  the  low-tension  vapor,  a  small  intra- 
venous of  epinephrine  hydrochloride  produced  the  worst  form 
of  irritability,  viz.,  ventricular  fibrillation,  which  usually  means 
immediate  death;  with  the  higher  tension  vapor  a  small  intra- 
venous of  epinephrine  produced  the  irregularities  which  had 
been  observed  to  result  from  the  low  percentages  of  chloroform 
alone. 

Of  considerable  importance  in  anesthesia  is  the  finding  of 
Cushny  and  Edmunds  that  the  heart  may  be  dilated  and  very 
weak  before  there  is  any  noteworthy  change  in  its  rate. 

Arteries. — The  vasoconstrictor  center,  after  a  primary  ir- 
ritation, is  depressed.  Bayliss,  who  has  done  much  work  in 
inhibition,  thinks  that  the  vasoconstrictor  center  is  changed  by 
chloroform  so  that  afferent  impulses  which  normally  result  in 
vasoconstriction,  now  result  in  vasodilatation.  (See  Sherring- 
ton's  theory  under  Strychnine.) 

In  some  cases  the  destructive  action  results  in  fatty  degenera- 
tion of  the  heart,  the  cardiac  ganglia,  and  even  the  arteries.  This 
is  particularly  likely  to  be  the  case  after  the  prolonged  admin- 
istration of  chloroform  for  anesthesia,  or  the  repetition  of  its 
administration  as  an  anesthetic  within  a  day  or  two.  In  anes- 
thesia, death  sometimes  takes  place  from  collapse,  due  to  depres- 
sion of  the  heart  and  arterial  muscles  or  to  ventricular  fibrilla- 


CHLOROFORM  2QI 

tion.  In  the  early  stages  of  the  anesthesia,  before  the  patient 
is  fully  anesthetized,  death  may  be  due  to  powerful  reflex  stimu- 
lation of  the  vagus  and  vasoconstrictor  centers,  the  latter  caus- 
ing abnormal  peripheral  resistance  against  a  weakened  heart. 
Muehlberg  and  Kramer,  by  the  injection  of  a  few  minims  of 
chloroform  into  the  carotid  artery  or  jugular  vein  of  laboratory 
animals,  obtained  intense  stimulation  of  the  vagus  and  vaso- 
contrictor  centers  with  heart  failure. 

Respiratory. — There  is  a  decided  depression  of  the  respiratory 
center,  preceded  by  a  very  short  period  of  stimulation.  In  some 
cases  respiratory  paralysis  is  the  cause  of  death,  and  in  experi- 
ments with  the  much  diluted  vapor  the  respiration  regularly 
ceases  before  the  heart;  but  the  heart  is  too  weak  to  permit 
resuscitation.  In  the  throat  and  bronchi,  if  the  vapor  is  prop- 
erly diluted,  it  is  not  irritating  and  may  even  be  soothing,  so  that 
cough  or  bronchial  irritation  may  be  less  after  the  anesthesia 
than  before  (Bennett). 

Nervous  System. — The  effects  are  practically  those  of  ether, 
the  cerebral  and  spinal  depression,  however,  following  more 
rapidly  and  from  a  much  smaller  amount  of  drug.  The  highest 
intellectual  functions  are  depressed  first,  then,  in  succession, 
the  emotional  and  motor,  the  cerebellar,  the  spinal,  and  finally 
the  medullary.  By  removing  the  pia  from  a  portion  of  the  cord 
to  exclude  that  portion  from  the  action  of  the  drug,  Bernstein 
tried  to  find  the  exact  site  of  action  of  chloroform.  On  lightly 
anesthetizing  the  animal  he  found  that  on  irritating  the  afferent 
nerves  whose  cells  \vere  in  the  excluded  area  reflexes  could  be 
obtained  involving  motor  cells  in  the  chloroformized  parts  of 
the  cord,  i.  e.,  the  motor  cells  where  not  paralyzed.  But  on 
irritating  the  afferent  nerves  whose  fibers  passed  through  the 
chloroformized  part  of  the  cord,  there  was  no  motor  response  at 
all.  Therefore,  he  concluded,  the  action  of  chloroform  must 
be  on  the  first  synapse  or  the  intermediate  neuron  of  the  afferent 
system,  the  same  structure,  probably,  that  is  excited  by  strych- 
nine. (See  Fig.  37.)  With  larger  amounts  of  chloroform  the 
motor  cells  or  their  synapses  are  also  paralyzed. 

Eye. — In  complete  anesthesia  the  pupil  is  rather  contracted, 
and  of  about  1.5  to  3  mm.  in  diameter,  i.  e.,  two-thirds  the  diam- 
eter of  the  ether  pupil. 

Elimination  is  chiefly  by  the  lungs  and  is  rapid.  Traces  are 
also  found  in  the  urine;  also  in  milk  and  fetal  blood. 

Kidneys. — Figures  as  to  the  occurrence  of  albuminuria  after 
ether  and  chloroform  vary  considerably  with  the  different  writers. 
After  41  ether  anesthesias  Babaci  and  Bebi  noted  albuminuria  in 
35  per  cent.;  while  after  54  chloroform  anesthesias,  albuminuria 


2Q2  PHARMACOLOGY    AND    THERAPEUTICS 

occurred  in  only  18  per  cent.,  i.  e.,  ether  proved  twice  as  likely 
to  produce  albuminuria  as  chloroform.  On  following  up  their 
observations  \vith  experiments  on  dogs,  guinea-pigs,  and  rabbits, 
these  investigators  found  that  though  ether  more  readily  causes  a 
passing  or  functional  albuminuria,  chloroform  is  more  prone  to 
produce  destructive  changes,  i.  c.,  fatty  degeneration  and  perma- 
nent inflammatory  lesions.  Hence  chloroform,  though  less  prone  to 
produce  albuminuria,  is  more  dangerous  to  the  kidneys  than  ether. 

Metabolism. — Chloroform  tends  to  produce  fatty  changes  in 
various  organs,  in  the  following  order  of  extent  and  frequency: 
liver,  kidneys,  spleen,  heart,  arteries  and  cardiac  ganglia,  and 
perhaps  the  lungs. 

The  main  effects  on  metabolism  are  due  to  the  marked  de- 
structive changes  in  the  liver  leading  to  necrosis.  There  is  a 
decrease  in  the  storage  of  glycogen,  and,  as  a  consequence,  an 
increase  of  sugar  in  the  blood.  In  the  urine  there  is  increase  in 
phosphates,  chlorides,  sulphates,  and  total  nitrogen,  the  am- 
monia nitrogen  being  increased  while  the  urea  is  decreased. 
The  urine  sometimes  contains  sugar,  acetone,  and  allied  bodies, 
and  cystin,  leucin,  or  tyrosin.  These  effects  are  evidences  of 
increased  destructive  metabolism  with  incomplete  oxidation. 

Therapeutics  of  Chloroform,  Aside  From  its  Use  as  Anes- 
thetic.— Externally. — (i)  In  liniments,  as  a  riibcfacicnt  for  mus- 
cular, joint,  and  neuralgic  pains.  (2)  On  cotton  in  a  decayed 
tooth  for  toothache. 

Internally. — (i)  As  a  mild  and  pleasant  carminative  in  flatu- 
lence or  colic — the  \vater  or  spirit.  (2)  As  an  antemetic  in  re- 
fractory cases  of  vomiting — one  dram  of  the  water  every  hour. 
(3)  As  antihysteric  and  cerebral  sedative — the  spirit. 

The  Chloroform  habit  is  not  uncommon,  the  sweet  taste  and 
narcotic  action  making  the  drug  a  rather  pleasant  dose.  In 
some  cases  it  is  rubbed  into  the  gums.  The  effects  of  the  habit 
are  similar  to  those  of  the  chloral  habit.  (See  Chloral  Hydrate.) 

ETHER   AND    CHLOROFORM    AS    GENERAL   ANESTHETICS 

When  one  of  these  drugs  is  administered  in  sufficient  amount 
to  put  the  patient  into  a  state  of  coma,  with  muscular  relaxation 
and  the  abolition  of  nearly  all  reflexes,  the  patient  is  in  a  condi- 
tion of  "complete  general  anesthesia."  The  study  of  general 
anesthesia  is,  then,  a  study  in  toxicology;  and  the  production  of 
ether  or  chloroform  anesthesia  is  the  production  of  acute  ether 
or  chloroform  poisoning,  the  patient  being  drugged  into  a  state 
of  narcosis  bordering  on  collapse. 

The  objects  of  general  anesthesia  are:  to  abolish  pain,  con- 
sciousness, and  muscular  resistance.  To  be  useful  as  a  general 


ETHER  AND  CHLOROFORM  AS  GENERAL  ANESTHETICS   293 

anesthetic  a  drug  must  be  very  rapidly  absorbable,  must  act 
quickly  to  produce  narcosis,  and  must  be  very  rapidly  eliminated; 
and  it  must  be  capable  of  producing  muscular  relaxation  as  well 
as  complete  unconsciousness,  i.  e.,  abolishing  cerebral  and  spinal 
activity,  without  dangerous  depression  of  the  vital  medullary 
centers  or  any  permanent  effect  upon  the  central  nervous  system. 

As  these  drugs  are  highly  volatile  and  their  vapor  is  rapidly 
absorbed  by  the  lungs,  their  administration  by  inhalation  is 
preferred  as  being  more  controllable  and  more  easily  continued 
for  a  long  time;  but  a  sufficient  dose  by  mouth  or  rectum  or  vein 
will  also  produce  anesthesia. 

We  shall  take  up  ether  anesthesia  first,  then  compare  chloro- 
form anesthesia  with  it. 

For  general  anesthesia,  ether  is  regularly  administered  by 
inhalation,  the  vapor  being  diluted  with  air  or  oxygen  and  ab- 


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(                             INDUCTION                           «       FULL   SURGICAL    ANAESTHESIA      „ 

Fig.  39.  —  Vapor  pressure  of  ether  in  tidal  air  for  induction  and  maintenance 
of  full  anesthesia.  Partial  pressure  of  vapor  in  millimeters  of  mercury  (Karl 
Connell  in  "Operative  Therapcusis,"  edited  by  A.  B.  Johnson,  D.  Appleton  &  Co. 


sorbed  by  the  lungs.  To  avoid  dangerous  irritation  of  the 
respiratory  passages  and  to  prevent  asphyxia,  the  ether  vapor 
must  be  diluted  with  air  for  administration  by  the  lungs,  just 
as  Hoffmann's  anodyne  must  be  diluted  with  water  for  adminis- 
tration by  the  stomach.  "To  establish  and  maintain  full  surgical 
anesthesia  the  blood  flowing  past  the  neuron  must  contain 
constantly  about  \  per  cent,  of  ether,  or,  in  terms  of  tension, 
50  mm.  of  ether  —  and  it  is  only  by  high  percentages  of  vapor  in 
the  pulmonary  air  that  the  arterial  blood  can  be  recharged 


294 


PHARMACOLOGY    AND   THERAPEUTICS 


constantly  to  proper  anesthetic  tension  and  the  central  nervous 
system  reduced  to  a  state  of  quiet  anesthesia  within  reasonable 
time"  (Connell).  Therefore  to  induce  anesthesia  quickly  it  is 
necessary  that  the  air-ether  mixture,  which  is  begun  at  about  4 
per  cent,  to  avoid  primary  irritation,  shall  rapidly  reach  1 6  to  24 
or  even  28  per  cent.  To  maintain  anesthesia  it  must  be  kept  at 
about  6  to  7  per  cent.  With  a  proper  adjustment  of  the  amount 
of  air  and' the  amount  of  ether  a  patient  may  generally  be  kept 
anesthetized  for  a  long  period,  even  for  three  or  four  hours,  with- 
out any  serious  symptoms  manifesting  themselves. 

For  convenience  of  study  the  production  of  ether  anesthesia 
may  be  divided  into  four  stages : 

1 .  Local  action  and  blunted  perceptions. 

2.  Intoxication. 

3.  Stupor,  or  partial  surgical  anesthesia. 

4.  Coma    and    muscular    relaxation,    or    complete,  surgical 
anesthesia. 

Beyond  this  stage  we  get  collapse,  and  finally  death,  a  highly 
regrettable  outcome  of  our  voluntary  poisoning. 

It  must  be  borne  in  mind  that  there  is  no  sharp  line  of  demar- 
cation between  these  several  stages,  and  that  some  of  the  symp- 


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Fig.  40. — Zones  of  ether  anesthesia  (Karl  Connell  in  "Operative  Therapeusis," 
edited  by  A.  B.  Johnson,  D.  Appleton  &  Co.,  1915). 

toms  of  one  stage  may  occur  with  some  of  the  symptoms  of 
another  stage.  The  division  into  stages  is  arbitrary,  and  is 
purely  for  convenience  of  study. 

The  First  Stage. — This  is  characterized  by  local  irritation, 
followed  by  local  numbness  and  blunted  senses. 

i.  Subjective  Symptoms. — The  ether  vapor  causes  irritation  of 


ETHER  AND  CHLOROFORM  AS  GENERAL  ANESTHETICS   295 

nose,  throat,  and  bronchi,  producing  a  sensation  of  choking  or 
lack  of  air  and  a  tendency  to  cough.  Soon  the  lips,  throat,  and 
nose  become  numb,  there  is  ringing  in  the  ears,  and  the  percep- 
tions become  dulled,  so  that  voices  sound  rather  distant  and  only 
things  close  by  are  noticed ;  but  the  patient  can  answer  questions 
and  may  talk.  As  he  loses  consciousness  he  feels  as  if,  no  matter 
what  happens,  he  is  powerless  to  lift  even  a  finger  to  help  himself; 
but  he  is  in  a  dreamy,  resigned  state,  and  doesn't  really  care  what 
does  happen. 

2.  Objective  Symptoms. — The  skin  soon  becomes  warm  and 
flushed,  the  pupils  are  dilated  from  excitement  or  from  irritation 
of  the  nose  and  throat,  the  heart  is  rapid,  and  arterial  pressure 
is  raised  from  the  reflex  stimulation  of  the  vasoconstrictor  center. 
Respiration  is  also  reflexly  stimulated,  but,  because  of  the  cough 
and  the  irritation  of  the  respiratory  tract,  there  is  resistance  to 
breathing,  hence  it  is  irregular. 

The  second  stage  is  characterized  by  intoxication,  or  drunk- 
enness, similar  to  that  from  alcohol.  The  highest  centers  of 
the  cerebrum — those  which  exert  judgment,  self-restraint,  etc.— 
the  intellectual  centers,  are  depressed,  and  the  emotional  and 
the  lower  animal  tendencies  are  more  or  less  freed  from  the 
normal  intellectual  control.  So  the  patient  is  childish,  or  may 
sing,  or  shout,  or  rave,  or  swear.  He  may  push  away  the  inhaler, 
or  try  to  get  up.  He  may  repeat  over  and  over  something  that 
the  doctor  has  said,  and  may  make  ugly  comments  on  the  char- 
acters of  his  attendants — in  fact,  he  is  drunk.  Though  his 
perceptions  are  dulled,  he  is  still  sensitive  to  pain.  On  recovery 
from  the  anesthesia  he  has  no  memory  of  this  stage. 

The  skin  is  flushed  and  may  show  an  ether  rash;  and  because 
of  the  resistance  to  respiration  and  the  necessity  at  this  stage  of 
giving  rather  concentrated  vapor,  it  may  become  somewhat 
cyanotic.  If  the  stomach  contains  food,  there  may  be  vomiting. 
The  pupils  are  dilated  and  react  to  light,  and  there  may  be  rolling 
of  the  eyeballs  or  strabismus,  with  the  eyelids  wide  open.  The 
heart  continues  somewhat  rapid  and  there  may  be  raised  blood- 
pressure.  If  the  patient  is  an  alcoholic,  very  fat;  or  robust  and 
athletic,  this  stage  is  rather  prolonged;  and  a  very  large  amount 
of  ether,  or  a  vapor  concentrated  even  up  to  30  per  cent.,  or  the 
addition  of  chloroform,  may  be  required  to  complete  the  anes- 
thesia. 

The  third  stage  is  that  of  stupor,  i.  c.,  unconsciousness  from 
which  one  can  be  aroused  only  with  difficulty.  The  pupils  are 
contracted  as  in  sleep,  the  heart  is  strong  and  regular  and  slower 
than  before  (though  not  slower  than  normal),  the  breathing  is 
deep  and  regular,  the  color  of  the  skin  is  good. 


2Q6  PHARMACOLOGY   AND   THERAPEUTICS 

The  intoxication  stage  is  over,  but  there  is  not  complete 
anesthesia,  for  if  the  knife  is  used  in  this  stage,  the  patient  will 
wince,  or  may  be  aroused  by  the  pain  and  try  to  get  up.  The 
muscular  relaxation  is  also  incomplete.  The  pupil  dilates  with 
pain  and  contracts  readily  to  light.  The  patient  may  be  kept  in 
this  stage  for  any  length  of  time,  or  may  quickly  be  brought  into — 

The  fourth  stage,  which  is  characterized  by  great  muscular 
relaxation  and  complete  unconsciousness,  from  which  the  patient 
cannot  be  aroused,  i.  e.,  coma. 

Most  of  the  voluntary  muscles  are  relaxed.  An  arm  or  a  leg 
raised  in  the  air  falls  limp,  and  the  face  is  expressionless  from 
relaxation  of  the  face  muscles.  The  sphincter  ani  is  one  of  the 
last  of  the  voluntary  muscles  to  be  paralyzed.  The  respiratory 
muscles,  of  course,  are  not  paralyzed.  Smooth  muscle  loses  its 
tone  less  readily  than  voluntary  muscle,  and  intestinal  peristalsis 
is  sometimes  observed  on  opening  the  abdomen.  The  skin  is 
usually  flushed  and  hot,  and  is  covered  with  sweat  (hence  the 
need  of  protecting  the  patient  from  catching  cold) .  In  the  mouth 
and  throat  saliva  and  mucus  are  abundant.  The  pupils  are  in 
mid-dilatation  and  react  so  sluggishly  to  light  that  their  contrac- 
tion may  be  difficult  to  detect.  The  eye  reflexes  disappear,  the 
absence  of  the  corneal  or  conjunctiva!  reflex  being  one  of  the 
indications  that  the  patient  is  well  anesthetized.  The  heart  is 
regular  and  of  fair  force.  Its  rate  is  moderately  increased. 
Arterial  pressure  is  good,  but  in  prolonged  anesthesia  alowly 
falls.  The  respiration  is  regular  and  may  be  stertorous  or 
snoring,  or  may  be  impeded  by  the  tongue  or  the  collection  of 
saliva  and  mucus,  large  amounts  of  which  are  secreted  in  the 
throat  and  bronchi  (the  throat  must  be  kept  clean,  the  jaw  and 
tongue  kept  forward).  The  temperature  falls,  so  that  the  patient 
must  be  kept  well  covered.  All  sensation  and  nearly  all  the 
reflexes  are  abolished.  This  is  complete  surgical  anesthesia,  a  state 
in  which  the  patient  may  be  kept  for  a  considerable  length  of  time. 
The  anesthetist  recognizes  this  stage  when  the  corneal  reflex  is 
absent,  and  the  raised  arm  falls  limp,  i.  e.,  is  completely  relaxed. 

If  the  patient  passes  beyond  this  stage,  he  goes  into  collapse, 
with  depression  of  the  vasoconstrictor  and  respiratory  cen- 
ters and  of  the  heart  muscle;  the  pupils  usually  become  dilated 
and  do  not  react  to  light. 

The  common  danger-signs  in  ether  anesthesia  are: 

1.  Increasing  weakness  or  increasing  rapidity  or  irregularity 
of  the  pulse.     It  should  be  remembered  that  the  heart  may  be 
quite  weak  before  its  rate  increases. 

2.  Slow,  shallow  respiration,  with  cyanosis. 

3.  Pupil  dilated  and  without  reaction  to  light. 


ETHER  AND  CHLOROFORM  AS  GENERAL  ANESTHETICS   297 

Recovery. — In  recovery  from  the  anesthesia  the  third  and 
second  stages  may  be  passed  through  slowly,  and  there  is  a 
tendency  for  the  patient  to  remain  asleep  until  awakened  by 
nausea  or  vomiting  or  some  other  disturbing  factor.  But  there 
may  be  a  period  of  struggling  and  incoherent  speech,  followed  by 
a  deep,  quiet  sleep;  or  a  period  of  prolonged  quiet  with  regular 
breathing  as  if  the  patient  is  deep  in  anesthesia,  and  then  sud- 
denly a  cry,  or  vomiting,  or  an  attempt  to  get  up.  A  careless  or 
inexperienced  anesthetist  may  allow  such  a  partial  recovery 
before  the  end  of  the  operation,  or  even  before  the  surgeon  begins 
work,  this  state  of  "false  anesthesia"  being  recognized  only 
when  the  patient  moves  or  gives  signs  that  he  is  going  to  vomit. 
It  is  a  standing  rule  that  if  the  pupil  reacts  readily  to  light,  more 
of  the  anesthetic  is  required. 

Vomiting  is  expected  when,  the  pulse  remaining  good,  there 
are  a  long  pause  in  the  breathing  and  a  paling  of  the  face.  The 
vomitus  consists  of  swallowed  mucus  and  saliva,  and  any  other 
material  that  may  be  in  the  stomach,  such  as  food.  As  muscular 
relaxation  prevents  its  full  expulsion,  the  head  should  be  turned 
to  one  side,  to  allow  the  vomitus  to  run  out  of  the  mouth;  other- 
wise the  vomitus  may  be  drawn  into  the  lungs. 

After-effects. — 1.  Usual — (a)  Vomiting  is  a  regular  sequel  of 
ether  anesthesia;  and  nausea  may  persist  for  two  or  three  days, 
with  disgust  for  food,  headache,  lassitude,  and  sometimes  a  per- 
sistent taste  of  ether.  The  vomiting  may  be  due  to  irritation  of 
the  stomach  by  the  ether  in  the  swallowed  secretions;  it  is  said 
to  be  absent  usually  in  rectal  or  intravenous  anesthesia  or  in- 
tratracheal  insufflation.  The  taste  of  ether  is  due  to  suggestion, 
or  to  the  slow  excretion  of  the  last  portions  of  the  ether.  It  has 
been  attributed  to  a  condition  of  acidosis.  If  it  persists  after  a 
few  hours,  the  stomach  may  be  lavaged  with  a  solution  of  sodium 
bicarbonate;  or  3<D-grain  (2  gm.)  doses  of  sodium  bicarbonate  may 
be  administered,  or  i  ounce  (30  gm.)  of  glucose  (Beddard)  or 
olive  oil  ( Graham) .  Thirst  is  marked,  but  because  of  the  vomiting 
tendency  cannot  be  allayed.  Most  surgeons  allow  very  little 
liquid  for  the  first  few  hours,  e.  g.,  one  or  two  teaspoonfuls  of 
water  each  hour  or  half  hour.  The  thirst  is  less  if  the  patient 
drinks  freely  of  water  two  or  three  hours  before  the  operation. 
It  may  be  absent  if  hypodermoclysis  of  saline  is  kept  up  during 
the  operation  (see  Saline  Infusion). 

(b)  Distention  oj  stomach  and  intestines  with  gas,  sometimes 
lessened  by  carminatives,  stupes,  enemata,  colon  irrigations,  the 
continuous  rectal  drip  method  of   Murphy,  or  by  pituitary  or 
physostigmine  hypodermatically. 

(c)  Pain  in  tlie  back,  between  the  shoulders,  or  in  the  small 


298  PHARMACOLOGY   AND   THERAPEUTICS 

of  the  back.     Lessened  by  change  of  posture,  special  pillows, 
etc. 

2.  Untoward  Sequelae. — (a)  Of  the  respiratory  organs — bron- 
chitis, pneumonia,  edema  of  the  lungs,  or  the  lighting  up  of  a 
quiescent  tuberculous  process  in  the  lung.  The  danger  of  pneu- 
monia is  said  by  Miiller  to  be  greatly  increased^  ether  is  admin- 
istered a  second  time  within  a  few  days.  N.  G.  Davis  and  also 
Stursberg  have  brought  forward  some  evidence  that  in  some 
cases  the  post-ether  respiratory  'troubles  may  be  due  to  the 
patients  catching  cold  rather  than  to  ether  irritation.  Stursberg, 
in  experimenting  with  dogs,  found  that  if  the  ether  were  allowed 
to  evaporate  freely  there  was  a  surface  chilling,  with  pronounced 
rise  in  arterial  pressure  from  reflex  contraction  of  the  internal 
arteries.  This  did  not  occur  from  chloroform.  With  the  open 
cone,  too,  the  ether  refrigeration  by  evaporation  at  the  mouth- 
piece makes  the  inhaled  vapor  very  cold,  and  this  in  itself  might 
be  enough  to  irritate  the  bronchi  and  lungs.  Hence  the  resort 
to  warmed  vapor  on  the  part  of  some  anesthetists,  the  container 
being  placed  in  warm  water.  There  is  evidence,  both  pro  and 
con,  as  to  the  value  of  warming  the  vapor.  Seelig  (1911)  found 
that  the  gas  inhaled  caused  no  cooling  in  the  trachea,  but  that 
the  evaporating  vapor  cooled  the  air  about  the  patient. 

(b]  Of  the  kidneys — albuminuria  and  sometimes  acute  ne- 
phritis. 

(c)  Postoperative  'gastric  or  intestinal  paralysis. — Treated  by 
strychnine  and  lavage,  intestinal  irrigations,  enemata,  or  hypo- 
dermics of  pituitary  or  physostigmine. 

(d}  Local  injuries,  as  conjunctivitis,  from  ether  getting  into  the 
eye,  or  from  injury  done  by  the  finger  of  the  anesthetist  in  testing 
the  corneal  reflex;  and  a  sore  tongue  from  the  use  of  tongue  forceps, 
or  from  the  passing  of  a  suture  through  the  tongue  to  hold  it 
forward. 

Helpful  or  Preventive  Measures  in  Ether  Anesthesia.— 
i .  Preliminary  anesthetization  uith  nitrous  oxide  or  ethyl  chloride. — 
This  practically  does  away  with  the  irritation,  struggling,  and 
intoxication  of  the  first  and  second  stages.  The  ether  is  begun 
when  the  patient  is  in  the  third  stage.  There  may  be  a  long 
movement  of  cessation  of  breathing  as  the  change  is  made,  but 
regular  breathing  is  soon  resumed. 

2.  Preliminary  anesthetization  with  chloroform. — This  short- 
ens the  first  and  second  stages.     In  athletes,  alcoholics,  or  the 
obese  it  is  easier  to  bring  on  the  anesthesia  with  chloroform, 
ether  being  substituted  as  soon  as  the  patient  is  well  anesthetized. 

3.  Preliminary    administration     of    sedative     drugs. — About 
half  an  hour  before  the  operation  morphine  sulphate,  \  grain 


INDICATIONS   FOR   ETHER   AS   ANESTHETIC  299 

(0.015  gm.),  or  morphine  sulphate,  |  grain  (o.oi  gm.)  with 
scopolamine  hydrobromide,  7-^  grain  (0.0006  gm.),  or  chlore- 
tone,  15  grains  (i  gm.)  by  mouth;  or  by  rectum,  30  grains  (2  gm.) 
of  hedonal  or  i  to  2  drams  (4-8  c.c.)  of  paraldehyde.  These  quiet 
the  patient's  mind  and  lessen  fear,  anxiety,  and  other  psychic 
disturbances.  They  also  expedite  the  anesthetization  and  make 
less  of  the  anesthetic  necessary.  Crile  has  shown  that  shock  is 
less  if  the  patient's  mind  is  at  ease.  The  morphine  is  a  powerful 
depressant  of  the  respiratory  center,  and  may  cause  contraction 
of  the  pupil. 

4.  Injection  of  atr  opine  sulphate — T£T   grain  (0.0006  gm.), 
or  -fa  grain  (0.0012  gm.),  to  stimulate  the  respiratory  center, 
to  lessen  the  secretions  of  saliva  and  mucus,  and  to  prevent 
primary  vagus  stimulation.     It  may  interfere  with  the  usual 
pupil  reactions. 

5.  Warming  the  'vapor  and  diluting  with  oxygen  instead  of 
air. — Gwathmey  gives  data  of  experiments  on  cats  which  indi- 
cate that  either  of  these  procedures  lessens  the  toxicity  of  both 
ether  and  chloroform.     He  warms  the  ether  with  a  thermolite 
bottle  or  by  setting  the  container  in  hot  water.     This  at  least 
tends  to  counteract  the  great  coldness  about  the  mouth  caused 
by  the  evaporation  of  more  or  less  of  the  vapor. 

6.  Reassuring  the  patient. — Crile  states  that  psychic  distur- 
bances, fear,  anxiety,  etc.,  distinctly  increase  the  chance  of  col- 
lapse; and  in  very  nervous  cases,  especially  those  with  hyper- 
thyroidism,  he  takes  time — even  days — to  get  the  patient  into 
a  calm  mental  state. 

7.  Having  the  stomach  empty. — To  avoid  the  danger  of  vomit- 
ing food  and  having  it  drawn  into  the  lungs.     This  is  accom- 
plished ordinarily  by  abstention  from  food  for  several  hours,  but 
in  an  emergency  by  lavage. 

8.  Preliminary  feeding  with  carbohydrates  and  water — just  long 
enough  before  the  operation  to  allow  the  stomach  to  empty  itself. 
This  has  been  shown  to  prevent  fatty  degeneration  and  necrosis  of 
the  liver  and  to  lessen  postoperative  nausea.    Fat  food,  however, 
promotes  the  liver  destruction.     It  has  been  demonstrated  that 
the  dangers  of  ether  are  greater  in  starvation  and  fatigue,  so  it  is 
considered  wise  not  to  leave  the  patient  without  food  and  rest 
for  too  long  a  period  before  the  operation. 

9.  Administering  sodium  bicarbonate,   ^   ounce   (15   gm.)   in 
solution  by  rectum  half  an  hour  before  the  anesthetic. 

INDICATION   FOR   ETHER   AS    GENERAL   ANESTHETIC 

Ether,    especially    with    proper    preventive    precautions,    is 
preferred  to  chloroform  in  almost  all  cases,  including  those  with 


300  PHARMACOLOGY   AND   THERAPEUTICS 

heart  or  kidney  disease.  It  is  not  employed  in  cases  with  severe 
bronchial  or  pulmonary  inflammation,  or  in  very  old  age,  where 
the  ether  intoxication  might  result  in  rupture  of  a  sclerosed 
vessel  or  in  some  other  injury.  In  brain  surgery  Horsley  prefers 
chloroform  because  of  the  danger  of  a  rise  in  general  arterial 
pressure  from  ether  and  the  resultant  extensive  oozing  of  blood; 
while  Crile  uses  ether  because  of  the  special  danger,  in  such  sur- 
gery, of  depression  of  the  medullary  centers. 

When  ether  fails  to  bring  about  muscular  relaxation,  as  in 
some  alcoholics  or  very  robust  athletic  persons;  or  when  the 
secretions  of  the  throat  are  so  abundant  as  to  become  dangerous, 
chloroform  alone,  or  chloroform  followed  by  ether,  may  be 
employed.  It  is  reported  that  in  hot  countries  and  at  high  alti- 
tudes anesthesia  with  ether  is  difficult  to  obtain;  but  Squire 
(Lancet,  1913)  reports  the  satisfactory  use  of  ether,  even  with 
the  temperature  120°  F.  in  the  shade. 

Where  a  very  quick  and  very  transitory  effect  is  desired,  as 
in  obstetrics,  chloroform  has  usually  been  preferred.  But  a 
number  of  cases  of  fetal  death  from  chloroform  are  reported ;  and 
in  some  cases,  though  the  child  is  born  alive,  it  never  breathes 
because  of  the  depression  of  the  respiratory  center. 


CHLOROFORM   ANESTHESIA 

In  the  production  of  anesthesia  by  chloroform  there  are  four 
stages,  as  in  ether  anesthesia,  and  the  symptoms  are  the  same  in 
nature.  But  chloroform,  properly  diluted  with  air,  is  not  un- 
pleasant to  the  patient,  is  scarcely  irritating  to  nose  and  throat, 
and  is  more  prompt  in  producing  anesthesia,  hence  the  first  and 
second  stages  are  comparatively  short  and  not  so  disagreeable, 
and  the  stage  of  intoxication  is  seldom  troublesome.  With 
chloroform  a  patient  may  be  anesthetized  in  from  two  to  five 
minutes;  with  ether  it  may  take  ten  or  fifteen  minutes.  The 
recovery  is  correspondingly  rapid.  Again,  the  amount  of  ether 
required  is  much  greater,  it  being  reckoned  in  ounces,  while  that 
of  chloroform  is  reckoned  in  drams.  In  chloroform  anesthesia 
the  face  is  usually  pale  rather  than  flushed,  and  the  breathing  is 
quiet;  in  fact,  so  different  is  this  from  the  ether  effect  that  it 
sometimes  worries  the  anesthetist  or  surgeon  who  has  been 
regularly  employing  ether. 

Chloroform  would  therefore  have  some  decided  advantages 
over  ether  were  it  not  for  the  fact  that  it  is  less  safe.  The  ad- 
vantages are:  (i)  Smaller  dose.  (2)  Simplicity  of  administra- 
tion— a  small  container  and  small  mask,  a  good  thing  in  field 
work;  or  a  few  drops  on  a  handkerchief.  (3)  Easier  and  pleas- 


CHLOROFORM   ANESTHESIA  301 

anter  for  patient.  (4)  Less  marked  stage  of  intoxication.  (5) 
Anesthesia  more  quickly  produced.  (6)  Anesthesia  more  quickly 
recovered  from.  (7)  No  bronchial  or  lung  irritation.  (8) 
Respiratory  mucus  and  saliva  not  excessive.  (9)  Nausea  and 
vomiting  less  common  after-effects.  (10)  Chloroform  is  not 
inflammable,  and  its  vapor  does  not  make  an  explosive  mixture 
with  air. 

These  are  decided  advantages  in  the  administration  of  an 
anesthetic,  yet  in  spite  of  them  ether  is  preferred  because  chloro- 
form is  more  dangerous. 

The  special  dangers  of  chloroform  anesthesia  are — (i)  Early 
heart  failure;  (2)  the  cardiac  depression  with  limited  margin  of 
safety;  (3)  delayed  chloroform  poisoning. 

The  First  Danger. — This  may  come  from  too  concentrated 
vapor  at  the  start,  or  from  ventricular  fibrillation,  the  result  of 
too  weak  vapor  (see  Pharmacologic  Action).  In  the  laboratory 
it  is  not  uncommon  that  when  a  dog  is  made  to  inhale  con- 
centrated chloroform  its  heart  will  be  promptly  slowed,  and  in 
some  cases  will  stop  and  not  beat  again.  Death  from  concen- 
trated vapor  takes  place  before  enough  chloroform  has  been 
absorbed  to  cause  death  by  systemic  action.  But  if,  before  the 
inhalation,  a  dog  is  given  a  hypodermatic  of  a  large  dose  of 
atropine,  or  if  his  vagus  nerves  are  cut,  even  very  concentrated 
chloroform  does  not  cause  a  stoppage  of  the  heart  at  all.  The 
cessation  of  the  heart-beat  must,  therefore,  be  due  to  excessive 
vagus  activity.  But  this  stoppage  of  the  heart  is  also  prevented 
if  the  laryngeal  nerves  are  cut  or  if  the  throat  is  anesthetized 
with  cocaine;  therefore  the  effect  is  a  reflex  one,  and  the  stimu- 
lation of  the  vagus  is  the  result  of  the  irritant  action  of  the 
chloroform  upon  the  throat. 

It  has  been  surmised  that  many  of  the  chloroform  casualties 
have  taken  place  in  this  way,  for  they  have  occurred  in  the  first 
few  moments  of  the  administration,  before  the  surgeon  had  begun 
to  operate  and  before  the  stage  of  full  anesthesia  had  been  reached 
(90  per  cent,  of  casualties  take  place  in  the  first  fifteen  minutes — 
Gwathmey).  This  possibility  of  excessive  reflex  inhibition, 
therefore,  becomes  a  serious  matter. 

Ordinarily,  it  is  impossible  to  kill  an  animal  by  excessive  vagus 
stimulation,  for  after  a  brief  period  the  heart  will  go  on  beating 
again  in  spite  of  the  vagus.  But  in  the  administration  of  a  gas 
by  the  lungs  the  area  of  absorption  is  large;  and  the  pulmonary 
blood,  charged  heavily  with  vapor,  passes  instantly  to  the  left 
heart  and  poisons  its  muscles. 

Cases  are  not  reported  of  excessive  vagus  inhibition  from  the 
use  of  ether  as  an  anesthetic,  but  Muehlberg  and  Kramer  have 


302  PHARMACOLOGY   AND   THERAPEUTICS 

shown  that  an  injection  into  the  carotid  artery  of  as  little  as  2 
minims  of  ether  or  chloroform  can  cause  almost  instant  death 
in  a  rabbit.  They  also  show  that  even  if  vagus  inhibition  is 
prevented  the  heart  is  weakened.  The  conclusion  is  that  when 
death  takes  place  during  the  early  stages  of  chloroform  adminis- 
tration there  is  probably  either  ventricular  fibrillation,  or  a 
combination  of  three  conditions,  viz.:  (i)  Weakening  of  the  heart 
due  to  direct  action  of  the  poison.  This,  absorbed  by  the 
extensive  lung  surface,  makes  a  concentrated  solution  in  the 
pulmonary  blood  which  passes  at  once  into  the  left  heart  and  to 
the  coronaries;  (2)  reflex  vagus  stimulation,  and  (3)  reflex  vaso- 
constrictor stimulation.  The  combination  of  these  three  effects, 
viz.,  inhibition,  muscle  poisoning,  and  increased  peripheral 
resistance,  results  in  heart  failure. 

Levy  says  that  enough  chloroform  to  weaken  the  ventricles 
will  prevent  their  fibrillation.  On  the  other  hand,  if  the  chloro- 
form is  given  to  a  dog  in  sufficient  dilution  with  air  to  avoid 
the  local  irritation  of  the  throat,  both  the  vagus  center  and  the 
throat  soon  become  less  sensitive,  and  then  it  is  impossible  to 
produce  this  vagus  inhibition  with  any  strength  of  chloroform. 
Hence  the  excessive  reflex  activity  of  the  vagus  may  be  prevented 
by  avoiding  too  great  concentration  of  the  vapor  at  the  outset,  or 
by  a  preliminary  injection  of  a  large  dose  of  atropine,  or  by 
thorough  cocainization  of  the  pharynx  and  larynx. 

The  Second  Danger. — We  have  already  learned  that  chloro- 
form is  much  more  depressing  to  the  muscles  of  the  heart  and 
arteries  and  to  the  medullary  centers  than  is  ether.  This  de- 
pressing effect  is  seen  almost  from  the  start,  while  with  ether  such 
a  depression  is  not  noted  except  in  prolonged  anesthesia  or  from 
overwhelming  doses  of  concentrated  vapor.  In  addition,  the 
chloroform  has  a  special  affinity  for  the  heart  muscle,  so  that  it 
is  less  readily  discharged  from  it  than  ether.  Hence  resuscita- 
tion is  difficult. 

These  factors  make  the  margin  of  safety  for  chloroform  a 
narrow  one,  the  stage  of  complete  anesthesia  being  much  nearer 
the  stage  of  collapse  than  with  ether.  Furthermore,  when  col- 
lapse comes  on  from  ether,  the  patient  may  often  be  restored 
with  comparative  ease,  while  when  the  signs  of  collapse  appear 
from  chloroform  the  chances  of  recovery  are  small. 

The  Third  Danger. — In  the  last  few  years  a  great  many  cases 
have  been  reported  in  which  the  patient,  after  apparently  recover- 
ing from  chloroform,  would  pass  in  a  few  hours  or  days  into 
a  condition  of  marked  prostration,  delirium,  coma,  and  death. 
This  condition  has  become  known  as  delayed  chloroform  poisoning. 
and  it  has  been  the  subject  of  much  careful  study. 


CHLOROFORM   ANESTHESIA  303 

The  symptoms  appear  in  from  ten  hours  to  six  days  after  the 
anesthetization.  The  onset  may  be  gradual  or  sudden.  In  the 
former  the  patient  does  not  fully  recover  after  the  anesthesia, 
and  gradually  passes  into  a  state  of  prostration  with  delirium, 
coma,  and  death.  When  the  onset  is  sudden,  the  patient  re- 
covers from  the  anesthesia  and  is  apparently  doing  well,  and  the 
first  indications  of  anything  wrong  are  marked  cerebral  disturb- 
ance, with  the  sudden  appearance  of  periods  of  wild  delirium, 
with  shrieking  and  struggling,  alternating  with  periods  of  stupor 
or  coma.  There  may  be  vomiting  of  blood,  cyanosis,  jaundice, 
edema,  intestinal  or  renal  hemorrhage,  and  sweetish,  acetone 
breath.  The  urine  may  contain  albumin,  casts,  and  blood,  and  in 
addition  a  high  ammonia  nitrogen  and  low  urea  nitrogen,  and  in 
some  cases  acetone,  diacetic  acid,  and  beta-oxybutyric  acid.  The 
delirium  and  coma  are  followed  by  collapse,  death  taking  place 
twelve  to  sixty  hours  after  the  first  appearance  of  the  symptoms. 

Postmortem  examination  regularly  reveals  extensive  fatty 
degeneration  of  the  liver,  with  necrotic  areas  in  the  lobules  and 
scattered  hemorrhages,  frequently  some  fatty  degeneration  in 
the  kidney  tubules  with  hemorrhagic  areas,  and  sometimes  fatty 
degeneration  in  the  heart  and  arteries  (Howland  and  Richards). 
Degeneration  in  the  cardiac  ganglia  has  also  been  reported. 
There  may  be  hemorrhages  in  the  stomach  and  intestines  and 
in  the  serous  membranes. 

In  experiments  on  dogs  it  has  been  found  that  in  some  in- 
stances even  fifteen  minutes'  mild  anesthetization  from  chloro- 
form has  been  enough  to  produce  areas  of  fatty  degeneration  in 
the  liver.  And  it  is  believed  that  fatty  degeneration  of  the  liver 
of  some  degree  must  take  place  in  every  full  chloroform  anes- 
thesia, though  ordinarily  this  is  rapidly  recovered  from.  Miiller 
(1905)  and  Offergeld  in  the  same  year  demonstrated  that  in  ani- 
mals anesthetized  twice  within  a  few  days  the  changes  were  more 
pronounced,  and  delayed  chloroform  poisoning  more  likely  to 
follow.  It  has  also  been  shown  experimentally  that  a  prelim- 
inary impairment  of  the  kidneys  or  much  hemorrhage  favors  the 
liver  destruction. 

In  humans,  delayed  chloroform  poisoning  has  occurred  most 
commonly  in  children.  It  has  rarely  been  recovered  from.  In 
animal  experiments  carbohydrates  have  been  shown  to  be  pro- 
tective, and  A.  Weir  reports  one  case  of  recovery  following 
the  administration  of  15  gm.  of  glucose  in  500  c.c.  of  water  by 
stomach  (tube  through  nares)  every  four  hours,  and  10  gm. 
of  glucose  in  100  c.c.  of  water  by  rectum.  Graham  attributes 
the  toxemia  to  acids  formed  from  the  chloroform.  He  finds  that 
he  can  produce  similar  effects  by  hydrochloric  acid,  and  that 


304  PHARMACOLOGY   AND   THERAPEUTICS 

sodium  carbonate  in  hypertonic  solution  intravenously  markedly 
inhibits  the  production  of  the  lesions. 

•  The  conditions  which  favor  the  development  of  delayed 
chloroform  poisoning  are  believed  to  be:  Liver  abscess,  kidney 
disease,  anemia,  especially  that  due  to  hemorrhage,  alcoholism, 
obesity,  the  lymphatic  diathesis,  childhood,  previous  chloro- 
form anesthesia  within  two  or  three  days,  and  prolonged 
anesthesia. 

Several  observers  have  reported  acute  liver  atrophy  following 
chloroform. 

To  repeat,  then,  the  three  dangers  in  chloroform  anesthesia, 
which  are  slight  or  absent  in  ether  anesthesia,  are  the  following: 

1.  Sudden  death  before  complete  anesthesia  is  induced. 

2.  Small   margin   of  safety. — The   depression   of   heart   and 
arteries  and  of  the  vasoconstrictor  and  respiratory  center  makes 
a  small  margin  of  safety  between  the  stages  of  anesthesia  and 
collapse,  and  difficulty  in  restoring  the  patient  after  signs  of 
danger  are  manifest.     This  is  especially  true  in  persons  with  the 
lymphatic  diathesis. 

3.  Delayed  chloroform  poisoning. 

It  is  on  account  of  these  that  the  use  of  chloroform  has  been 
quite  generally  abandoned  as  a  general  anesthetic,  except  in  a 
few  special  types  of  cases. 

Possible  preventive  measures  are: 

1.  To  prevent  vagus  stoppage  of  heart — atropine,  ^  grain 
(o.ooi  gm.)  by  hypodermatic,  cocaine  to  throat,  or  well-diluted 
chloroform  at  the  start. 

2.  To  retard  cardiac  and  central  depression — oxygen,  avoid- 
ance of  too  long  a  period  of  starvation  before  the  operation,  and 
the  use  of  a  minimum  quantity  of  the  anesthetic. 

3.  To    lessen    or    check    the    fatty    degenerations — oxygen, 
glycogen-forming  food  (glucose,  sugar,  etc.),  alkalies,  and  avoid- 
ance of  too  long  a  period  of  starvation  before  the  anesthesia. 
Hunter  recommends  that  the  patient  be  given  a  nutritious  and 
easily  digestible  meal,  well  sweetened,  two  or  three  hours  before 
the  anesthetic. 

Contraindications  to  Chloroform. — Diabetes,  sepsis,  hem- 
orrhage, eclampsia,  conditions  of  much  enfeeblement,  fatty 
degeneration,  and  the  lymphatic  diathesis. 

Acidosis  in  General  Anesthesia. — The  development  of 
acidosis  following  anesthesia,  as  shown  by  the  appearance  of 
acetone,  diacetic  acid,  and  beta-oxybutyric  acid  in  the  urine,  is  a 
matter  of  considerable  importance. 

According  to  Ewing,  Becker  found  acetonuria  in  two-thirds 
of  all  anesthetized  patients,  the  condition  being  most  pronounced 


CHLOROFORM   ANESTHESIA  305 

in  children,  and  more  marked  in  women  than  in  men.  It  ap- 
peared in  the  first  or  second  portion  of  urine  passed,  and  per- 
sisted eight  or  nine  days.  Abram  found  acetone  in  25  cases,  and 
more  frequently  after  chloroform  than  after  ether.  Wallace  and 
Gillespie  found  it  hi  25  per  cent,  of  cases  before  operation  and  in 
about  60  per  cent,  after  operation.  Waldvogel  observed  it  in 
75  per  cent,  of  50  cases,  and  in  13  of  them  noted  diacetic  and 
beta-oxybutyric  acids. 

These  observations  indicate  the  marked  danger  of  general 
anesthesia  in  all  conditions  associated  with  acidosis,  such  as 
diabetes  and  the  various  toxemias,  especially  those  associated 
with  liver  degeneration.  Therefore  general  anesthesia,  whether 
from  chloroform  or  ether,  requires  special  consideration  in  dia- 
betes, eclampsia,  vomiting  of  pregnancy,  cyclic  vomiting,  acute 
yellow  atrophy  of  the  liver,  general  sepsis,  uremia,  and  in  those 
cases  of  intestinal  obstruction  with  marked  auto-intoxication. 
In  all  these  types  of  cases  the  dangers  of  chloroform  are  greater 
than  those  of  ether. 

Of  acetonuria,  Wallace  and  Gillespie  say  that  the  vomiting 
after  twelve  hours  is  regularly  related  to  the  amount  of  acetone, 
and  this  can  be  lessened  by  lavage  with  sodium  bicarbonate. 
But  for  administration  as  a  prophylactic  before  the  anesthesia 
glucose  is  to  be  preferred  to  sodium  bicarbonate. 

Effects  on  Infections  and  Immunity. — Graham-Rubin  (1907) 
showed  that  hypodermatics  of  alcohol,  ether,  or  chloroform 
rendered  rabbits  more  susceptible  to  systemic  infection  with 
streptococcus  and  pneumococcus;  and  Stewart  (1907)  showed 
that  this  was  especially  true  of  infections  to  which  immunity  was 
chiefly  phagocytic.  In  other  immunity  studies  also  it  has  been 
shown  of  alcohol,  which  is  of  the  same  class,  that  after  the  injec- 
tion of  an  antigen  it  retards  the  formation  of  the  antibodies. 
The  same  is  probably  true  of  ether  and  chloroform. 

Francois  (1910)  found  that  after  chloroform  or  ether  anes- 
thesia the  phagocytic  activity  of  the  leukocytes  was  lessened  or 
abolished,  and  that  this  effect  lasted  for  twenty-four  hours. 
Graham  (1910)  also  observed  that  the  phagocytic  power  was 
not  restored  for  many  hours.  He  noted  that  while  saline 
infusion  did  not  hasten  the  restoration,  olive  oil  by  rectum,  or 
lecithin,  o.i  gm.  subcutaneously,  shortened  the  period  of  phago- 
cytic depression.  But  Mann,  1916,  states  that  phagocytes 
that  have  been  subjected  for  four  to  six  hours  to  a  concentration 
of  ether  capable  of  maintaining  a  dog  under  surgical  anesthesia, 
do  not  exhibit  any  change  in  activity. 

Some  General  Remarks  about  Administration. — Before  the 
administration  the  patient  should  be  reassured  and  brought  into  a 


306  PHARMACOLOGY   AND   THERAPEUTICS 

calm  state  of  mind,  for  the  psychic  factor  is  important.  This 
is  the  idea  in  Crile's  "anoci-association." 

Skill  in  administering  a  general  anesthetic  involves  not  merely 
the  prevention  of  death,  but  also  the  leaving  of  the  patient  in 
the  best  possible  physical  and  mental  condition  after  the  opera- 
tion. With  both  chloroform  and  ether  the  danger  lies  in  over- 
concentration  of  the  vapor  or  surcharging  of  the  blood  by  too 
rapid  administration,  rather  than  in  the  total  quantity  of  the 
drug  employed  in  any  given  anesthesia. 

It  is  wise  to  avoid  anesthetizing  beyond  the  point  necessary, 
for  if  the  patient  becomes  too  deeply  anesthetized,  and  then,  by 
stoppage  of  the  administration,  is  allowed  to  come  back  to  the 
condition  of  surgical  anesthesia,  his  centers  are  more  depressed, 
and  he  is  in  a  weaker  and  less  resistant  state  than  if  he  has  been 
kept  steadily  at  the  proper  degree  of  anesthesia  throughout. 
To  administer  rapidly  a  large  quantity  of  concentrated  vapor, 
/'.  e.,  to  "push"  the  ether  or  chloroform  when  the  patient  unex- 
pectedly shows  signs  of  recovery,  adds  to  the  depression  of  the 
respiratory  and  vasoconstrictor  centers;  and  it  is  unjustifiable  to 
try  and  cover  up  the  faults  of  carelessness  or  inexperience  by 
such  a  method.  It  is  better  to  proceed  carefully,  even  though 
the  surgeon  is  kept  waiting. 

RECTAL   OR   COLONIC   ANESTHESIA 

Ether  is  sometimes  given  by  rectum,  the  bowel  being  thor- 
oughly cleansed  beforehand.  It  may  be  given  with  oxygen  or 
oil  as  the  diluent.  The  opportunity  for  free  exit  of  the  vapor 
is  considered  a  necessity.  Gwathmey's  oil-ether  colonic  method 
is  to  give  by  rectum  one  hour  before  the  operation  a  mixture  of 
morphine  alkaloid,  gr.  |  (0.008  gm.),  paraldehyd,  i  dram  (4  c.c.) 
and  ether  and  olive  oil,  each  3!  drams  (14  c.c.),  and  then  to  use  a 
mixture  of  i^  ounces  (45  c.c.)  of  olive  oil  and  4^  ounces  (135  c.c.) 
of  ether  as  the  main  anesthetic  about  twenty  minutes  before  the 
operation.  The  ether  vaporizes  by  the  body  heat,  leaves  the 
oil,  is  absorbed,  and  is  perceptible  in  the  breath  in  three  or  four 
minutes.  If  a  lightening  of  the  anesthesia  is  required  he  extracts 
some  of  the  oil,  and  uses  a  Connell  breathing  tube. 

Rectal  anesthesia  is  a  means  of  avoiding  the  distress  of  the 
first  stage  and  the  irritation  of  the  respiratory  tract;  it  is  said 
to  lessen  the  post-ether  nausea  and  vomiting.  It  is  sometimes 
followed  by  hemorrhage  from  the  bowel  or  by  diarrhea  or  colitis 
from  irritation  of  the  bowel,  so  must  be  used  with  great  care. 
The  author  has  learned  of  a  case  of  colonic  anesthesia  in  which 
death  followed  enormous  distention  and  rupture  of  the  colon. 


ANESTHESIA   BY   INTRATRACHEAL   INSUFFLATION  307 

This  was  presumably  due  to  the  combination  of  three  factors, 
viz.,  the  expansion  of  the  ether  vapor  by  the  warmth  of  the  body, 
the  non-resistance  of  the  bowel  owing  to  its  loss  of  muscular  tone, 
and  the  lack  of  a  free  exit  for  the  gas.  Cunningham  reports  a 
death  in  a  case  of  amebic  colitis. 

The  special  value  of  rectal  anesthesia  is  in  operations  about  the 
head  and  neck,  or  in  patients  with  inflammatory  conditions  of  the 
respiratory  tract. 

INTRAVENOUS  GENERAL  ANESTHESIA 

The  intravenous  route  was  early  tried  with  chloroform  and 
was  given  up  as  too  dangerous.  Then  Burkhardt  in  1911  used 
ether,  5  per  cent,  in  normal  saline  at  82.4°  F.  (28°  C.),  and  found 
it  suitable.  By  this  method  apparently  the  regulation  of  the 
degree  of  anesthesia  is  easy,  and  the  breathing  from  the  begin- 
ning is  regular.  Complete  anesthesia  is  attained  within  five 
minutes,  and  its  maintenance  is  dependent  on  keeping  a  proper 
balance  between  the  amount  of  ether  introduced  and  that 
excreted  by  the  lungs.  Connell  says  that  to  establish  anesthesia 
it  takes  50  c.c.  per  minute  of  5  to  7  per  cent,  ether  for  from  two  to 
five  minutes.  On  stopping  the  inflow,  return  to  consciousness  is 
prompt.  The  large  quantity  of  saline  predisposes  to  heart 
failure  and  pulmonary  edema,  and  may  result  in  abnormal 
oozing  at  the  wound.  The  use  of  a  vein  involves  the  risks  of 
thrombosis  and  embolism.  The  high  percentage  of  ether  at  the 
point  of  introduction  may  produce  hemolysis.  A  preliminary 
dose  of  morphine  with  atropine  or  scopolamine  is  customary. 

Paraldehyd  has  been  recommended  for  intravenous  anes- 
thesia by  Noel  and  Soutter  (1913).  From  5  to  15  c.c.  with 
an  equal  amount  of  ether  are  dissolved  in  150  c.c.  of  i  per  cent, 
saline,  and  injected  at  the  rate  of  about  5  to  10  c.c.  per  minute. 
A  mild  narcosis  comes  on  at  once,  and  there  is  deep  unconscious- 
ness in  one  minute.  This  ceases  soon  after  the  stoppage  of  the 
infusion.  Paraldehyd  is  detected  in  the  breath  in  ten  seconds. 
The  anesthesia  is  followed  by  easy  recovery  or  by  sleep.  It  is  a 
rapid  method  for  minor  operations  or  to  check  convulsions. 

Hogan  and  Hassler  say  that  paraldehyd  is  excreted  too 
rapidly  and  may  severely  irritate  the  larynx  and  bronchi. 

ANESTHESIA   BY   INTRATRACHEAL   INSUFFLATION 

In  1909  Meltzer  and  Auer,  working  with  dogs,  found  that 
the  ventilation  of  the  alveolar  air  could  be  accomplished,  and  that 
an  animal  could  be  kept  alive  and  in  good  condition  by  a  stream  of 
air  blown  through  a  tube  passed  down  the  trachea  nearly  to  the 


308  PHARMACOLOGY   AND   THERAPEUTICS 

bifurcation.  Even  after  curare  to  suspend  all  action  of  the 
striated  respiratory  muscles  the  animal  could  be  kept  alive  for 
hours.  In  fact,  they  had  discovered  a  wonderful  method  of 
performing  artificial  respiration. 

Then  they  found  that,  by  passing  the  stream  of  air  over 
ether,  they  could  anesthetize  the  animal,  and  at  the  same  time 
keep  up  a  sufficient  degree  of  positive  intrathoracic  pressure  to 
prevent  collapse  of  the  lungs  in  intrathoracic  surgery.  This 
method  has  now  become  extensively  employed  for  anesthesia 
with  ether  and  for  nitrous-oxide-oxygen  anesthesia. 

After  a  preliminary  anesthesia  to  depress  the  laryngeal 
reflex  a  silk- woven  catheter,  about  No.  22  French,  is  inserted 
through  the  glottis  until  the  teeth  are  at  a  mark  26  cm.  from  its 
end.  Then,  with  a  bellows  or  pump,  operated  by  foot  or  power, 
the  air  is  passed  through  or  over  ether  in  a  bottle  into  the  trachea. 
The  gases  from  the  lungs  make  their  escape  around  the  catheter, 
and  this  should  be  small  enough  to  leave  ample  room  in  the 
glottis.  The  apparatus  should  bear  a  manometer  for  recording 
the  pressure,  and  the  positive  pressure  should  not,  in  ordinary 
operations,  exceed  10  mm.  of  mercury,  and  in  intrathoracic 
surgery  20  mm.  At  the  end  of  the  operation  the  ether  is  shut 
off,  and  air  insufflated  for  several  minutes.  From  three  to  six 
times  a  minute  the  air-stream  should  be  stopped  to  permit 
collapse  of  the  lungs  and  the  expulsion  of  some  CO2  which  tends 
to  collect  in  the  alveoli.  The  ether-air  vapor  should  be  of  about 
6  or  7  per  cent,  strength. 

The  patient  makes  light  respiratory  movements,  but  the 
oxygenation  of  the  blood  goes  on,  irrespective  of  respiration. 
The  color  of  the  skin  is  good,  and  the  pulse  is  normal.  If  the 
patient  vomits  on  the  table,  or  if  blood  runs  down  the  throat,  as 
in  mouth  operations,  the  positive  pressure  of  the  escaping  gases 
prevents  aspiration  of  the  foreign  material  into  the  lungs. 

Following  the  anesthesia,  it  is  claimed,  there  seem  to  be  no 
bad  effects  from  the  tube  or  the  ether  vapor,  either  upon  the 
glottis,  the  trachea,  the  bronchi,  or  the  lungs,  even  in  the  pres- 
ence of  a  respiratory  disease;  and  usually  there  is  no  nausea  or 
vomiting.  But  in  intratracheal  insufflation  experiments,  Georg 
regularly  observed  injuries  to  the  alveoli  and  bronchioles, 
whether  the  pressure  was  low  or  high.  There  have  been  a  few 
deaths  reported,  generally  due  to  rupture  of  the  lungs  from  too 
great  pressure,  or  to  puncture  of  the  trachea  by  a  tube  that  is  too 
long.  This  last  produces  interstitial  emphysema.  These  dangers 
can  be  eliminated  by  having  a  short  tube,  a  manometer,  and  a 
careful  anesthetist,  or  by  a  safety  valve  set  at  20  mm.  of  pressure. 

Githens  and  Meltzer  (1911)  showed  that  double  the  lethal 


TREATMENT   OF   UNTOWARD    SYMPTOMS  309 

dose  of  strychnine  given  during  ether  anesthesia  by  intratra- 
cheal  insufflation  did  not  cause  the  death  of  a  single  animal. 

Pharyngeal  insufflation  is  produced  in  the  same  way  as 
intratracheal,  the  vapor,  however,  being  carried  merely  to  the 
pharnyx  by  a  Y  tube  bearing  on  each  fork  an  18  Fr.  soft-rubber 
catheter  with  double  eyelet  (the  Connell  nasopharyngeal  tube), 
to  be  passed  through  the  nostril. 


TREATMENT   OF  UNTOWARD    SYMPTOMS   IN   GENERAL 
ANESTHESIA 

(A}  Cyanosis. — If  this  is  due  to  excessive  secretion  or  the 
falling  back  of  the  tongue  or  jaw,  or  falling  of  the  paralyzed 
epiglottis  so  as  to  act  as  a  valve  over  the  glottis,  or  turning  of 
the  head  too  much  to  the  side,  the  condition  should  be  promptly 
remedied.  If  there  is  respiratory  weakness,  the  anesthetic 
should  be  stopped  and  a  respiratory  stimulant,  such  as  caffeine 
or  atropine,  injected  hypodermatically.  In  the  laboratory  a 
dog  lightly  anesthetized  with  ether  or  chloroform  is  likely  to 
become  conscious  and  recover  his  reflexes  if  a  hypodermic  of 
caffeine  is  administered.  If  necessary,  artificial  respiration  or 
pharyngeal  insufflation,  and  the  administration  of  oxygen  may  be 
resorted  to. 

(B)  A  rapid,  weak,  or  irregular  pulse  suggests  the  withdrawal 
of  the  anesthetic  and  the  use  of  saline  by  rectum  or  intravenously. 

(C)  For  marked  collapse,  the  following  is  the  treatment: 

1.  If  from  ether,  lower  head,  raise  feet,  and  give  free  access 
of  air.     If  from  chloroform,  keep  body  level,  or  may  precipitate 
heart  failure  (Bennett). 

2.  Keep  up  body  warmth,  using  hot  towels  and  hot  blankets. 

3.  Inject  hypodermatically  atropine,   caffeine,   or   camphor 
(not  ether  or  whisky).     Camphor  may  be  useful  in  chloroform 
collapse,  where  the  heart  is  the  organ  at  chief  fault.     (See  dis- 
cussion under  Camphor.) 

4.  If  an  ether  case,  give  hot  saline  by  rectum;  or  a  slow  in- 
travenous infusion  of  about  500  c.c.  of  normal  saline  solution,  to 
which  may  be  added  15  minims  (i  c.c.)  of  epinephrine  hydro- 
chloride  solution  or   15  minims  (i  c.c.)  of  pituitary  liquid.     In 
chloroform  anesthesia  Levy  and  Lewis  found  epinephrine  contra- 
indicated;  yet  we  have  surgical  reports  of  excellent  results  from 
adrenaline  even  after  chloroform. 

5.  If  necessary,  the  limbs  may  be  bandaged  from  fingers  and 
toes  up,  or  Crile's  pneumatic  suit  applied,  or  pressure  made  upon 
the  abdomen  with  weights  or  bandages. 

6.  Artificial   respiration   and   the  administration   of  oxygen 


310  PHARMACOLOGY   AND   THERAPEUTICS 

and  carbon  dioxide.  Henderson  says  that  carbon  dioxide  should 
not  be  given  in  concentration  above  6  per  cent.  Meltzer's 
method  of  artificial  respiration  by  intratracheal  insufflation  or 
by  a  suitable  mouth-cap  may  be  employed. 

7.  //  the  heart  stops,  try  rhythmic  thumping  or  pressure  over 
the  heart,  or  rhythmic  pressure  at  a  rate  of  30  per  minute  in  the 
epigastrium;  in  an  abdominal  operation  massage  heart  through 
the  diaphragm.  If  the  heart  has  ceased  to  beat,  inject  10 
minims  of  adrenaline  solution  and  10  minims  of  the  tincture 
of  digitalis  into  the  cavity  of  the  ventricle  or  beneath  the 
pericardium,  and  massage  vigorously.  The  author  has  resusci- 
tated dogs  in  this  manner. 

Ether,  whisky,  and  strychnine  hypodermatically  have  re- 
peatedly been  shown  to  increase  the  collapse,  and  electricity  to 
produce  fibrillation  and  stoppage  of  a  weak  heart.  In  chloro- 
form collapse  the  heart  is  very  feeble,  so  that  measures  to  increase 
the  peripheral  resistance  must  be  instituted  with  caution;  and 
Bennett  says,  "do  not  lower  the  head  end  of  the  body." 

Therapeutics. — The  objects  of  general  anesthesia  are:  to 
abolish  pain,  to  abolish  consciousness,  and  to  relax  muscle. 
General  anesthesia  may  be  employed: 

1.  In  surgical  cutting  operations. 

2.  To  set  a  fracture. 

3.  To  reduce  a  dislocation. 

4.  To  reduce  a  hernia. 

5.  To  permit  more  thorough  examination  for   diagnosis   of 
the  abdomen  or  an  injured  limb. 

6.  To  stop  convulsions  (tetanus,  strychnine  poisoning). 

7.  In  labor — at  the  time  of  the  expulsion  of  the  fetal  head  to 
stop  pain  (perineal  pain)  and  lessen  or  abolish  the  contractions 
of  the  uterus.      As  a  rule,  only  enough  chloroform  is  required 
for  this  to  wet.  well  the  chloroform  mask.     General  anesthetics 
tend  to  lessen  the  power  of  the  uterus  to  contract,  hence  to  some 
extent  favor  postpartum  hemorrhage.     Postpartum  operations 
are  preferably  done  under  ether. 

NITROGEN   MONOXIDE    (NITROUS    OXIDE) 

Nitrous  oxide,  N2O,  or  laughing-gas,  is  obtained  by  heating  a 
mixture  of  salts  containing  ammonium  nitrate.  It  is  marketed 
under  compression  in  steel  cylinders,  and  is  administered  by  a 
special  inhaler,  consisting  of  a  rubber  bag  and  mouth-piece  with 
exit  valves  for  the  expired  air.  It  received  the  name  of  laughing- 
gas  because  in  some  instances  the  inhalation  of  a  small  quantity 
of  it  produced  uncontrollable  hilarity.  A  bright,  glowing  stick 


NITROGEN   MONOXIDE    (NITROUS    OXIDE)  31 1 

plunged  into  nitrous  oxide  ionizes  it,  and  bursts  into  bright  flame, 
as  in  pure  oxygen ;  but  a  dull  glowing  stick  goes  out  and  animals 
and  plants  quickly  die  if  placed  in  the  gas,  for  they  cannot  bring 
about  dissociation  to  obtain  the  oxygen.  So  nitrous  oxide  will 
not  maintain  life,  and  if  used  pure,  quickly  produces  asphyxia. 
It  must,  therefore,  be  given  with  air  or  oxygen.  It  has  no  local 
action,  and,  after  absorption,  exists  in  simple  solution  in  the  blood 
plasma.  But  it  is  not  an  indifferent  gas,  like  nitrogen,  for  in 
85  or  90  per  cent,  strength  it  is  a  distinct  narcotic,  capable  of 
producing  very  rapidly  a  full  degree  of  unconsciousness,  though 
with  incomplete  muscular  relaxation.  Some  of  the  anesthesia 
has  been  attributed  to  asphyxia,  but  not  only  is  asphyxia  not 
necessary  in  the  anesthesia,  but  it  is  to  be  avoided  as  much  as 
possible.  When  air  is  used  as  the  diluent,  there  is  always  some 
asphyxia,  with  venous  congestion,  cyanosis,  and  raised  blood- 
pressure;  so  to  maintain  anesthesia  it  is  now  regularly  employed 
with  oxygen  as  the  diluent.  Teter  says  that  it  is  impossible  to 
avoid  asphyxia  with  less  than  1 1  per  cent,  of  oxygen. 

With  the  nitrous-oxide-oxygen  combination  the  production  of 
anesthesia  is  very  prompt,  and  the  recovery  almost  immediate. 
To  produce  the  anesthesia  it  may  be  necessary  to  add  some  ether. 
And  it  requires  such  skill  to  keep  the  patient  in  a  uniform  state  of 
anesthesia  of  sufficient  degree  without  asphyxia  that  it  is  custom- 
ary to  administer,  about  half  an  hour  before,  some  slowly  act- 
ing narcotic,  such  as  morphine  sulphate  with  atropine  or  scopol- 
amine.  Gatch  has  introduced  a  method  of  rebreathing  which 
not  only  saves  gas,  but  utilizes  the  patient's  own  carbon  dioxide 
for  the  double  purpose  of  stimulating  the  respiratory  center  and 
preventing  acapnia.  At  any  time  it  may  be  wise  to  add  some 
ether.  The  three  danger-signals  in  the  administration  are 
vomiting,  cyanosis,  and  slow  pulse.  A  few  deaths  are  reported. 

According  to  Crile,  with  the  same  degree  of  trauma  there  is 
only  one-fourth  as  much  shock  from  nitrous  oxide  as  from  ether. 
So  the  method  is  an  admirable  one  in  the  hands  of  an  expert. 
It  is  not  satisfactory,  however,  in  alcoholics,  the  obese,  and 
robust  athletic  persons.  It  is  contraindicated  in  children  under 
five  years,  because  of  the  ease  with  which  asphyxia  can  be  pro- 
duced in  such;  in  old  people  with  degenerative  lesions,  because 
of  the  high  blood-pressure  and  because  of  the  convulsive  move- 
ments in  case  of  asphyxia;  usually  in  brain  surgery  because 
of  increased  venous  flow;  in  cardiac  weakness  because  of  the 
raised  peripheral  resistance ;  and  in  any  case  in  which  it  will  not 
produce  anesthesia  without  cyanosis. 

The  nitrous  oxide  and  oxygen  combination  has  come  into 
considerable  use  as  the  anesthetic  of  choice  for  general  purposes. 


312  PHARMACOLOGY   AND   THERAPEUTICS 

It  is  especially  adapted  for  short  operations  and  obstetrics.  In 
the  latter  it  may  be  administered  early  to  produce  a  form  of 
''twilight  sleep,"  for  it  is  not  dangerous  to  the  fetus,  does  not  les- 
sen the  strength  or  frequency  of  the  uterine  contractions,  and  does 
not  predispose  to  postpartum  hemorrhage  (Ryder).  Nitrous 
oxide  and  air  are  still  much  employed  by  dentists  in  the  ex- 
traction of  teeth,  and  by  anesthetists  as  a  preliminary  to  ether 
to  avoid  the  disagreeable  first  and  second  stages. 


ETHYL   CHLORIDE 

Ethyl  chloride  (aethylis  chloridum),  C2H5C1,  is  a  highly  vola- 
tile and  inflammable  gas,  prepared  by  the  action  of  hydrochloric 
acid  upon  absolute  alcohol.  It  condenses  to  a  liquid  at  13°  C. 
(55.4°  F.),  and  is  kept  thus  in  sealed  tubes  under  pressure.  These 
tubes  are  made  with  a  minute  pin-hole  nozzle  covered  with  a  cap; 
and  on  removal  of  this  cap  the  liquid  issues  with  some  force  in  the 
form  of  a  very  fine  spray. 

Local  Action. — On  striking  the  warm  skin  it  vaporizes  with 
such  rapidity  that  it  freezes  the  tissues.  This  makes  a  local 
anesthesia  of  a  moment's  duration,  during  wrhich  a  small  cut,  as 
of  an  abscess  or  infected  finger,  or  a  puncture,  as  in  paracentesis 
of  thorax  or  abdomen,  may  be  made  without  pain.  The  freezing 
of  the  tissues  sometimes  results  in  sloughing.  The  spray  is 
sometimes  also  employed  in  facial  neuralgia. 

Systemic  Action. — To  produce  general  anesthesia  ethyl  chlo- 
ride is  vaporized  into  an  inhaler,  the  patient  being  brought 
into  a  state  of  anesthesia  in  from  one  to  two  minutes  with- 
out any  local  irritation,  but  with  incomplete  muscular  relaxa- 
tion. Recovery  when  the  anesthetic  is  stopped  is  almost  imme- 
diate, and  because  of  this  it  is  a  difficult  task  to  maintain  the 
anesthesia  for  any  length  of  time.  (Whiteford  has  kept  the 
patient  under  ethyl  chloride  for  thirty-five  minutes,  and  Wiessner 
for  fifty  minutes,  by  pouring  2  or  3  c.c.  on  the  mask  every  two 
minutes;  Montgomery  and  Bland,  for  fifty-four  minutes.) 

On  the  average,  5  gm.  will  produce  unconsciousness  and  abo- 
lition of  pain  in  one  or  two  minutes,  and  maintain  it  for  ten 
minutes,  but  the  reflexes  are  not  depressed  to  the  point  of  com- 
plete muscular  relaxation.  Because  of  its  concentrated  form  and 
ease  of  transportation,  it  being  a  liquid  in  glass  tubes,  and  be- 
cause of  its  cheapness  in  the  dose  used,  it  has  been  employed  in 
operations  of  short  duration,  in  dentistry,  and  as  a  preliminary 
to  ether  anesthesia.  Connell  says  that  severe  headache,  nausea, 
repeated  vomiting  and  severe  prostration  are  not  infrequent, 
that  "a  delayed  collapse  has  added  a  number  of  fatalities  to  the 


MAGNESIUM   SULPHATE    (EPSOM    SALT)  313 

score  of  this  anesthetic,"  and  that  "on  the  whole,  ethyl  chloride 
meets  no  necessity  in  anesthesia  which  cannot  be  better  supplied 
by  ether,  chloroform,  or  nitrous  oxide." 

Ethyl  bromide  resembles  ethyl  chloride  in  its  action,  but  is 
not  quite  so  volatile,  and  its  use  has  been  abandoned. 

Mixtures  of  these  anesthetics  should  not  be  employed. 


MAGNESIUM  SULPHATE  (EPSOM  SALT) 

In  1899  Meltzer  noted  paralysis  in  a  rabbit  from  the  intra- 
cerebral  injection  of  magnesium  sulphate,  and  in  1905  was 
joined  by  Auer  in  an  investigation  of  this  action.  They  found 
that  a  25  per  cent,  solution  applied  to  a  nerve-trunk  completely 
blocked  both  sensory  and  motor  impulses;  that  on  subcutaneous 
injection  there  was  complete  anesthesia  with  muscular  relaxa- 
tion lasting  for  two  or  three  hours  and  without  any  cathartic 
effect,  and  that  the  injection  into  the  spinal  canal  was  followed 
by  sensory  and  motor  paralysis  and  profound  narcosis.  The 
paralysis  began  in  the  hind  legs  and  spread  upward  until  it  in- 
volved the  anterior  extremities.  With  lethal  doses  the  blood- 
pressure  was  but  little  affected,  and  death  was  due  to  respira- 
tory paralysis. 

In  one  experiment  on  a  monkey  a  lethal  dose  was  given  in- 
traspinally.  Respiration  failed,  but  as  the  heart  continued  beat- 
ing, artificial  respiration  was  instituted.  After  seven  hours  the 
artificial  respiration  was  stopped,  and  the  animal  was  found  to 
be  still  incapable  of  spontaneous  respiration.  After  seven  hours 
more  the  artificial  respiration  was  again  stopped,  and  then  the 
animal  continued  to  breathe  without  aid.  During  all  the  period 
of  respiratory  paralysis  the  heart's  action  continued  good,  and 
there  was  evidently  no  cardiac  or  vasoconstrictor  depression. 

Meltzer  and  Lucus  found  that  after  its  subcutaneous  injection 
the  drug  was  eliminated  by  the  kidneys,  and  that  when  the  kid- 
neys were  impaired,  it  was  twice  as  poisonous,  and  might  have  a 
cumulative  action.  According  to  Meltzer  the  dominant  action 
of  magnesium  salts,  no  matter  what  the  mode  of  administration, 
is  depression  or  inhibition.  Intramuscularly  and  intravenously 
the  action  is  rapid  and  of  short  duration.  Intraspinally  the 
effect  lasts  twenty-four  hours.  There  may  be  slight  irritation  of 
the  kidneys,  retention  of  urine,  or  glycosuria  with  hyperglycemia. 
Canestro  (1910)  found  that  the  addition  of  a  small  amount  of 
epinephrine  made  it  less  toxic  to  the  respiratory  center.  That 
it  is  a  central  anesthetic  as  well  as  peripheral  has  been  fully 
established  by  Meltzer  and  his  associates.  Hyndman  and  Mitch- 
ener  (1910)  found  it  no  more  depressing  to  the  motor  area  of 


314  PHARMACOLOGY   AND   THERAPEUTICS 

the  brain  than  ether,  as  tested  by  electric  stimulation.  Cloetta 
showed  that  the  salts  do  not  penetrate  the  cells  of  the  brain  and 
do  not  act  like  the  volatile  anesthetics  of  the  alcohol  series. 

Afeltzer's  Theory  to  Explain  the  Anesthetic  Action  and  its 
Neutralization  by  Calcium. — Magnesium  readily  enters  the 
"synaptic  membrane"  (Sherrington)  between  the  neurons,  and 
interrupts  the  passage  of  afferent  nervous  impulses.  The 
synaptic  membrane  between  motor  nerves  and  muscle  are  more 
resistant  to  magnesium,  so  efferent  nervous  impulses  are  less 
readily  affected.  Calcium  enters  the  synaptic  membrane 
readily  and  displaces  or  neutralizes  there  the  obstructing 
or  inhibiting  magnesium.  When,  however,  magnesium  by  its 
long  presence  in  the  lymph  manages  to  enter  the  inside  of  the 
nerve-cell,  the  calcium  is  incapable  of  readily  dislodging  or 
neutralizing  it. 

Following  these  experiments  the  drug  has  been  used  for  the 
production  of  anesthesia  and  the  treatment  of  tetanus  and  other 
spasmodic  affections. 

Anesthesia. — J.  A.  Blake  and  many  others  used  the  intraspinal 
method,  and  concluded  that  the  action  was  too  uncertain  and 
likely  to  be  too  prolonged,  though  even  with  the  most  profound 
anesthetic  effects  the  heart's  action  remained  regular,  and  the 
blood-pressure  was  not  lowered.  But  Peck  and  Meltzer  (1916) 
have  reported  cases  of  its  intravenous  use,  employing  about  8  c.c. 
per  minute  of  a  6  per  cent,  solution.  Sensation,  consciousness, 
and  muscular  tone  were  more  or  less  abolished,  and  recovery 
took  place  within  a  few  minutes  of  the  cessation  of  the  adminis- 
tration. They  found  the  dose  very  variable.  Auer  and  Meltzer 
(1916)  were  able  to  obtain  in  dogs  a  stage  of  analgesia  with  re- 
laxed abdominal  muscles  while  the  respiration  remained  normal 
and  the  lid  reflex  was  fair  or  even  normal.  They  advise  against 
its  use  if  there  is  cardiac  insufficiency  or  acute  nephritis. 

Dawbarn,  and  also  Wainwright,  in  using  spinal  analgesia 
to  block  afferent  impulses  in  traumatic  shock,  found  that  when  the 
effect  of  a  rapidly  acting  local  anesthetic  wears  off,  the  shock 
may  reappear  and  the  patient  die,  death  being  merely  postponed 
an  hour  or  two.  In  two  cases  Dawbarn  employed  a  solution  of 
magnesium  sulphate  with  tropacocaine,  and  found  that  in  both  the 
nerve-blocking  began  quickly  and  continued  for  from  twenty-four 
to  forty-eight  hours,  i.  e.,  the  tropacocaine  began  the  anesthesia 
early,  and  the  magnesium  sulphate  continued  it.  Injected  along 
the  course  of  the  nerves  it  also  anesthetizes. 

Tetanus. — The  most  striking  effects  are  the  relief  from  pain 
and  the  cessation  of  the  spasms  so  that  swallowing  of  food  becomes 
possible.  The  dose  is  renewed  when  there  is  a  feeling  of  tight- 


MAGNESIUM   SULPHATE    (EPSOM   SALT)  315 

ness  about  the  chest  or  inability  to  swallow.  Meltzer  gives  the 
following  plan  of  treatment,  with  the  precautions:  In  mild  cases 
inject  subcutaneously  1.2  c.c.  of  25  per  cent,  solution  three  or 
four  times  a  day.  In  severe  cases  administer  intraspinally  i 
c.c.  of  25  per  cent,  solution  for  each  20  pounds  (10  kg.)  of  body 
weight,  or  for  children  0.5  c.c.  for  each  20  pounds.  If  the  symp- 
toms are  alarming,  as  in  spasm  of  pharynx,  larynx,  or  diaphragm, 
give  2  to  3  c.c.  per  minute  of  a  6  per  cent,  solution  intravenously 
till  the  dangerous  symptoms  subside  or  the  respiration  becomes 
shallow  or  too  slow.  If  from  the  intravenous  solution  the  res- 
piration becomes  depressed  a  small  amount  of  2.5  per  cent, 
calcium  chloride  intravenously  may  restore  it  almost  immediately 
and  this  may  be  supplemented  by  -^  grain  (i  mg.)  of  physostig- 
mine.  Never  continue  the  calcium  salt  beyond  the  restoration 
of  respiration  or  the  whole  magnesium  action  will  be  annulled  and 
the  tetanic  symptoms  recur.  If  there  is  suspended  respiration, 
intrapharyngeal  insufflation  or  some  other  method  of  artificial 
respiration  should  be  instituted,  and  if  necessary  continued  for 
hours.  For  respiratory  paralysis  from  intraspinal  administra- 
tion calcium  and  physostigmine  are  useless,  and  the  spinal  canal 
should  be  washed  out  several  times  with  Ringer's  solution. 

Owing  to  its  prolonged  action  magnesium  sulphate,  used 
intraspinally,  would  seem  to  be  particularly  valuable  and 
safe  in  the  convulsions  of  tetanus,  strychnine  poisoning,  and 
eclampsia,  and  in  preventing  shock  from  severe  traumatism. 
Used  intraspinally  or  injected  into  the  nerve,  it  has  been  sug- 
gested as  a  possible  measure  of  relief  in  refractory  sciatica. 

Besides  these  uses  the  drug  has  been  employed  intraspinally 
in  delirium  tremens,  intravenously  in  puerperal  strep tococcemia 
(Huggins  and  Harrar  report  good  results),  and  intravenously 
or  subcutaneously  in  chorea  and  spasmophilia.  Bryant  reports 
the  cure  of  a  purulent  cerebrospinal  meningitis  from  copious 
draughts  of  a  dilute  solution,  and  Wyatt-Smith  cures  of  non- 
amebic  dysentery  from  colon  irrigations.  It  is  to  be  remembered 
that  Auer  and  Meltzer  (1914)  found  that  it  might  be  absorbed 
from  the  small  intestine  with  fatal  effects. 

Locally,  a  saturated  solution  of  magnesium  sulphate  (it  is 
soluble  in  0.85  part  of  water)  has  been  much  employed  in  the 
form  of  a  wet  compress  as  a  local  application  to  reduce  the  pain 
in  neuralgia,  neuritis,  dermatitis,  and  burns.  Tucker  (1911)  re- 
ports good  results  in  epididymitis,  arthritis,  cellulitis,  and  ery- 
sipelas. (See  also  Saline  Cathartics.) 


316          PHARMACOLOGY  AND  THERAPEUTICS 

INTOXICANTS 
ALCOHOL 

Common  alcohol,  grain-alcohol,  ethyl  alcohol,  C2H5(OH),  is 
made  by  fermenting  a  sugar  solution  with  yeast  in  the  presence 
of  nitrogenous  substances.  The  sugar  may  be  that  of  a  fruit- 
juice,  or  that  prepared  from  starch  or  wood.  Along  with  the 
ethyl  alcohol  other  bodies  are  produced.  The  alcohol  of  com- 
merce is  obtained  by  distillation,  and  contains  amyl  alcohol  and 
other  bodies  which  constitute  its  "fusel  oil."  It  mixes  freely 
with  water,  ether,  and  chloroform,  and  is  a  solvent  for  alkaloids, 
many  salts,  resins,  volatile  oils,  and  two  of  the  fixed  oils,  viz.r 
castor  oil  and  croton  oil.  It  does  not  dissolve  the  other  fats  and 
fixed  oils,  or  adhesive  plaster  or  collodion. 

Preparations. — Pure  alcohol  is  to  be  had  in  three  strengths, 
viz.: 

(a)  Dehydrated  alcohol  (absolute  alcohol],  at  least  99  per  cent, 
of  ethyl  alcohol;  (b)  Alcohol,  95  per  cent.  (U.  S.  P.,  94.9)  by 
volume.  This  is  not  the  alcohol  of  commerce,  but  is  known  to 
the  trade  as  "deodorized  alcohol"  or  "cologne  spirit."  It  is 
ordinary  grain  alcohol  with  the  fusel  oil  removed,  and  has  a 
specific  gravity  of  0.8 1 6  at  60°  F.  (c)  Diluted  alcohol,  48.9  per 
cent,  by  volume,  made  with  equal  volumes  of  water  and  alcohol, 
which  shrink  on  mixing. 

For  internal  use,  one  or  other  of  the  alcoholic  drinks  is  regu- 
larly employed,  rather  than  pure  alcohol;  and  these  contain,  in 
addition  to  the  alcohol,  substances  which  give  them  their  char- 
acteristic odor  and  taste.  A  large  number  of  pharmaceutic 
preparations  contain  alcohol  either  as  solvent  or  preservative, 
and  certain  proprietary  remedies  with  a  large  content  of  alcohol 
are  especially  popular.  Women  habitues  frequently  drink  in 
secret,  and  may  consume  large  quantities  of  eau  de  cologne, 
Florida  water,  witch-hazel,  or  some  proprietary  remedy.  De- 
natured alcohol,  for  use  tax  free,  is  a  mixture  of  100  parts  of 
grain  alcohol,  10  parts  of  wood-alcohol,  and  0.5  part  of  benzin. 

The  alcoholic  drinks  in  common  use  are  of  five  classes: 

1.  The  malt  liquors. 

2.  The  red  and  white  wines. 

3.  The  fortified  wines. 

4.  The  distilled  liquors,  or  spirits. 

5.  The  elixirs. 

i.  The  malt  liquors  are  prepared  from  starchy  substances, 
usually  grain.  The  grains  are  ground  and  boiled  with  water  to 
form  a  mash,  /.  c.,  to  hydrolyze  the  starch  and  form  a  starch  paste. 
On  the  addition  of  barley  malt,  which  contains  the  ferment  dias- 


ALCOHOL  317 

tase,  the  starch  changes  and  goes  into  solution  as  dextrin,  mal- 
tose, and  dextrose.  To  this  solution  are  added  hops,  which  yield 
a  bitter  principle  and  a  hypnotic  substance;  then,  after  filtration, 
the  liquid  is  fermented  by  yeast  to  the  desired  degree.  Then  the 
yeast  is  killed  by  heat,  the  fermentation  being  always  stopped 
before  all  the  sugars  are  destroyed.  Cheap  beers  have  quassia, 
gentian,  wormwood,  or  other  bitter  substitutes  for  the  hops. 

The  malt  liquors  contain  from  3  to  7  per  cent,  of  alcohol  by 
volume,  together  with  about  the  same  percentage  of  extractive 
matter,  composed  of  dextrin,  maltose,  and  colloidal  material, 
and  acids  of  the  fatty  series,  chiefly  acetic.  They  all  contain 
CO2  gas,  so  are  effervescent.  Strauss  states  that  they  average 
about  0.145  gm-  °f  purin  bodies  per  liter.  They  are  acid  in 
reaction,  have  the  action  of  bitters  upon  the  appetite,  and  are 
nutritive.  In  the  stomach  they  immediately  set  free  the  con- 
tained CO2.  The  sugar  bodies  also  tend  to  generate  gas,  and  the 
colloidal  material  to  interfere  with  the  activity  of  the  digestive 
ferments.  None  of  the  malt  liquors  are  pharmacopceial,  but 
those  in  common  use  are:  Beer,  ale,  porter,  and  stout. 

Beers  ("lager  beer")  are  prepared  by  slow,  cool  fermentation 
(38°  F.)— Blyth  says  i2°-i40  C.  (53°-57°  F.)— by  bottom  yeast, 
i.  e.,  a  yeast  which  sinks.  Imported  beer  is  usually  stronger 
than  domestic,  a  little  higher  proportion  of  alcohol  being  desired 
for  preservation  purposes. 

Ales  (in  British  countries  called  "beer")  are  fermented  at 
ordinary  temperatures  (56°-68°  F.)  by  top  yeast,  i.  e.,  a  yeast 
that  floats.  They  average  somewhat  more  alcohol  than  beer. 

Porter  and  stout  are  ales  in  which  the  malt  has  been  highly 
kilned  or  roasted,  so  that  some  of  it  is  changed  to  caramel.  As  a 
consequence  they  have  a  very  dark  color  and  a  caramel  taste, 
and  are  rich  in  dissolved  substances.  Stout  is  the  richer  and 
stronger  of  the  two. 

The  liquid  extracts  of  malt  used  in  medicine  are  beers  contain- 
ing a  small  percentage  of  alcohol,  a  large  amount  of  nutritive 
extractive,  chiefly  sugars,  and  unchanged  extract  of  malt. 

2.  The  wines  are  made  by  yeast  fermentation  of  saccharine 
fruit-juices.  They  vary  considerably  in  their  composition,  but 
regularly  contain  from  8.5  to  15  per  cent,  of  alcohol  by  volume, 
with  glycerin,  tartaric  acid,  acetic  and  other  fatty  acids,  alde- 
hydes, furfurol,  amylic,  cenanthylic  and  other  alcohols,  certain 
esters  which  are  produced  on  long  standing  and  give  to  the  wine 
its  mellowness  and  bouquet,  and  albuminous  and  other  colloidal 
extractive  matters.  The  red  wines  contain  tannic  acid;  the 
sweet  wines  contain  dextrose.  Kahlbaum  of  Berlin  has  separated 
12  different  esters  from  wines  in  common  use,  acetic  ether  being 


318  PHARMACOLOGY  AND  THERAPEUTICS 

that  most  frequently  encountered.  Wines  are  not  so  nutritive 
as  the  malt  liquors,  and  many,  such  as  claret,  Burgundy,  Rhine, 
and  Moselle  wines,  contain  little  or  no  sugar.  With  age  the 
tannin,  alcohol,  and  acids  decrease,  and  the  glycerin  and  esters 
increase.  The  largest  percentage  of  esters  is  0.3  (Dupre).  The 
wines  are  not  recognized  by  the  Pharmacopoeia. 

A  sweet  wine  is  one  that  contains  free  sugar;  a  dry  wine  is  one 
that  is  entirely  or  almost  free  from  sugar,  practically  all  the  sugar 
having  been  changed  in  the  fermentation.  A  light  wine  is  one 
that  contains  a  low  proportion  of  alcohol ;  a  strong  or  heavy  wine, 
one  that  is  strong  in  alcohol.  A  sparkling  wine  is  one  that  con- 
tains CO2  in  solution,  as  champagne  and  sparkling  Burgundy; 
these  wines  bubble  or  effervesce  when  the  cork  is  withdrawn,  and 
because  of  the  CO2  gas  are  often  readily  borne  in  cases  of  refrac- 
tory vomiting. 

Red  wine  is  prepared  by  fermenting  the  juice  of  red  grapes  in 
the  presence  of  their  skins.  It  contains  tannic  acid,  and  is 
more  astringent  than  white  wine.  Claret  is  a  common  red  wine, 
which,  because  of  its  astringency,  is  sometimes  used  as  a  gargle 
in  sore  throat. 

White  wine  is  made  from  grapes  that  have  been  freed  from 
seeds,  stems,  and  skins.  It  usually  does  not  contain  tannic  acid. 
Sauterne  and  Chablis  are  examples. 

Fermented  apple  and  pear  ciders  are  of  the  class  of  wines, 
as  they  are  prepared  from  sugar-containing  fruit-juices.  They 
contain  much  malic  acid  and  usually  sugar,  and  a  large  quantity 
of  extractive  matter. 

3.  The  fortified  wines  are  certain  wines  whose  percentage  of 
alcohol  has  been  increased  by  the  addition  of  a  distilled  liquor 
made  from  grapes,  raisins,  figs,  or  sweet  potatoes.     In  ordinary 
fermentation  the  yeast  activity,  even  under  the  most  favorable 
conditions,  ceases  altogether  at  about  15  to  17  per  cent,  of  alcohol 
by  volume,  so  that  this  is  the  limit  of  strength  to  be  obtained  by 
simple  fermentation.     The  fortified  wines  have  a  strength  be- 
tween this  and  that  of  the  distilled  liquors. 

Sherry  (vinum  xericum),  port  (vinum  portense),  and  Madeira 
are  the  common  fortified  wines,  and  they  contain  from  17  to  25 
per  cent,  of  alcohol  by  volume.  Sherry  is  quite  acid,  and  con- 
tains little  or  no  sugar.  Port  is  less  acid,  but  has  from  3  to  7  per 
cent,  of  sugar.  The  fortified  wines  are  not  official. 

4.  The  distilled  liquors,  or  spirits,  are  prepared  by  distilling 
any  fermented  liquor.     By  the  distillation  the  sugars,  the  non- 
volatile acids  and  extractive  matters  are  left  behind,  and  the  alco- 
hols, the  ethers,  and  any  volatile  acids  are  distilled  over.     On 
long  standing  the  alcohols  and  acids  react  upon  each  other  and 


ALCOHOL  319 

develop  the  esters,  which  give  the  liquor  its  bouquet.  The 
distilled  liquors,  none  of  which  are  now  pharmacopceial,  are 
separated  into  two  general  classes,  according  to  their  origin,  viz. : 

(a)  Those  Obtained  from  Malt  Liquors. — In  common  use  are 
whisky  and  gin. 

Whisky  (spiritus  frumenti)  is  described  in  the  Pharma- 
copoeia of  1900  as  "an  alcoholic  liquid  obtained  by  the  dis- 
tillation of  the  mash  of  fermented  grain  (corn,  rye,  wheat, 
barley),  and  not  less  than  four  years  old.  It  contains  44  to 
55  per  cent,  by  volume  of  ethyl  alcohol,  and  in  addition  minute 
quantities  of  various  other  alcohols,  ethers,  etc.,  carried  over 
in  the  distillation,  and  acid  esters  formed  on  standing."  Cheap 
whiskies  are  aged  by  ozone  and  electricity  in  three  days,  and 
are  darkened  with  prune-juice  to  give  them  the  color  that  is 
properly  derived  from  storage  in  oak  barrels.  The  fusel  oil  of 
whisky  is  composed  chiefly  of  amyl  alcohol  and  furfurol. 

Scotch  and  Irish  whiskies  have  a  somewhat  smoky  odor  from 
being  distilled  over  peat  fires,  or  being  made  from  malt  that  is 
dried  over  peat  fires.  They  are  said  to  contain  traces  of  creosote 
and  other  empyreumatic  oils.  Irish  whiskies  usually  contain  a 
rather  high  percentage  of  alcohol. 

Gin  is  prepared  by  distillation  of  fermented  rye  mash,  and 
redistillation  of  the  product  with  juniper  berries,  or  sometimes 
other  aromatics,  such  as  cardamom  or  coriander.  It  contains  a 
high  percentage  of  alcohol,  60  to  70  per  cent.,  and  some  volatile 
oil  of  juniper,  on  account  of  which  it  is  diuretic  and  carminative. 
It  is  a  favorite  remedy  among  women  for  dysmenorrhea.  Gin  is 
sometimes  called  the  "compound  spirit  of  juniper." 

(0)  Those  Distilled  from  Fermented  Saccharine  Fruit-juices. — 
These  are  known  as  brandies.  Apple-brandy  and  pear-brandy 
are  prepared  from  apple  or  pear  cider.  But  the  brandy  of  com- 
merce and  of  medicine  is  that  from  grape-wine.  It  is  known 
also  as  "Cognac"  or  "French  brandy." 

Brandy  (spiritus  vini  gallici)  is  not  now  official.  It  is  de- 
scribed by  the  Pharmacopoeia  of  1900  as  "an  alcoholic  liquid 
obtained  by  the  distillation  of  the  fermented,  unmodified  juice 
of  fresh  grapes,  and  not  less  than  four  years  old.  It  contains 
46  to  55  per  cent,  by  volume  of  ethyl  alcohol,  besides  enanthic 
and  other  esters." 

Rum  is  the  distillate  from  fermented  molasses,  and  has  a 
slight  taste  of  brown  sugar.  It  varies  greatly  in  strength,  but  is 
frequently  much  stronger  than  brandy. 

5.  The  elixirs  are  aromatic,  sweetened,  hydro-alcoholic 
liquids.  They  are  artificial  mixtures,  and  contain  various  flavor- 
ing substances,  sugar,  and  a  large  percentage  of  alcohol.  They 


320  PHARMACOLOGY  AND  THERAPEUTICS 

include    the    pharmaceutic   elixirs,    and    the   liqueurs,    cordials, 
crimes,  etc., 

The  following  table  of  percentages,  calculated  to  volume 
from  Hutchinson's  report,  gives  an  idea  of  their  alcohol  and 
sugar  content: 

ALCOHOL  CANE-SUGAR 

Chartreuse 50  per  cent,  by  volume  34  per  cent. 

Creme  de  menthe 50        "  27 

Benedictine 60       "  32         " 

Absinthe 67 

Drinks  which  contain  much  absinthe  (Vermouth,  Wormwood), 
as  absinthe  cordial  (and  even  perhaps  Vermouth  wine),  have  a 
peculiar  action  upon  the  brain,  and  their  habitual  use  leads  to 
mental  depression,  epileptiform  convulsions,  and  a  state  of 
insanity.  Belgium,  Holland,  France,  and  Switzerland  have 
passed  laws  prohibiting  the  manufacture  of  absinthe  cordial,  and 
since  October  1,1912,  the  United  States  has  forbidden  its  importa- 
tion. 

None  of  the  elixirs  are  employed  for  the  administration  of 
alcohol  as  medicine,  but  the  pharmaceutic  elixirs,  which  contain 
from  25  to  35  per  cent,  of  alcohol,  are  employed  as  vehicles  for 
bitter  and  bad-tasting  drugs.  The  elixir  of  calisaya  is  a  favorite 
soda-fountain  tipple. 

There  are  two  official  elixirs : 

Elixir  aromaticum,  aromatic  elixir  (compound  spirit  of 
orange,  1.2;  syrup,  37.5;  alcohol,  about  25  per  cent.,  and  water 
to  make  100).  It  is  used  solely  as  a  flavored  vehicle. 

Elixir  glycyrrhizcB — aromatic  elixir,  containing  12  per  cent,  of 
fluidextract  of  glycyrrhiza.  It  is  used  solely  as  a  flavoring 
vehicle.  The  licorice  is  incompatible  with  acids. 

In  addition  to  the  above,  the  following  mixed  drinks  are 
worthy  of  note: 

A  highball  is  whisky  diluted  with  a  carbonated  water,  some- 
times with  the  addition  of  lemon-peel. 

A  cocktail  is  an  aromatic  or  bitter,  strongly  alcoholic,  mixed 
drink,  to  be  taken  before  meals  as  an  appetizer.  Its  basis  is 
usually  gin. 

A  milk- punch  is  a  mixture  of  sugar,  milk,  and  whisky,  served 
cold.  It  may  have  a  little  nutmeg  sprinkled  over  its  surface.  Its 
flavor  is  improved  by  a  dash  of  Jamaica  rum. 

A  brandy  milk-punch  is  made  with  brandy  instead  of  whisky. 

An  egg-nog  is  a  milk-punch  shaken  up  with  an  egg  and  cracked 
ice,  and  strained. 

It  must  be  borne  in  mind  that  most  liquid  pharmaceutic 


ALCOHOL  321 

preparations  contain  alcohol,  and  some  of  them  are  nearly  all 
alcohol.  Many  of  the  nutritive  peptone  mixtures  on  the  market 
(panopepton,  liquid  peptonoids,  etc.)  owe  much  of  their  nutritive 
value  to  the  15  or  20  per  cent,  of  alcohol  present. 

The  medicinal  dose  of  a  distilled  liquor  is  4  drams  (15  c.c.), 
that  of  sherry  or  port,  about  twice  as  much.  A  sherry-glass  holds 
i  ounce  (30  c.c.). 

Pharmacologic  Action. — Having  a  great  affinity  for  water 
and  being  a  coagulant  of  protein,  alcohol  tends  to  irritate  and 
destroy  cells.  It  is,  therefore,  a  general  protoplasmic  poison. 
The  power  to  coagulate  protoplasm  gives  alcohol  its  value  as  a 
hardening  agent  for  anatomic  specimens. 

Micro-organisms. — In  the  preparation  of  alcoholic  liquors 
by  fermentation  it  is  found  that  the  activity  of  the  yeast  life  is 
retarded  when  the  alcohol  reaches  about  10  per  cent,  of  the 
liquid,  and  is  completely  checked  when  the  alcohol  is  about 
15  per  cent.  Typhoid  bacilli  were  completely  destroyed  in 
twelve  hours  in  a  mixture  of  equal  parts  of  red  wine  (12  per  cent.) 
and  water  (Sabrazes  and  Marcandier).  It  is  evident,  there- 
fore, that,  when  its  application  is  prolonged,  alcohol  has  anti- 
septic properties.  (See  table  in  "Antiseptics.")  Harrington 
and  Walker  found  that  a  solution  of  about  70  per  cent,  strength 
has  a  greater  germicidal  power  than  stronger  solutions.  Strong 
alcohol  (60  to  90  per  cent.)  has  been  used  for  the  preservation  of 
plant  and  animal  specimens. 

Skin.—  Applied  to  the  skin  and  allowed  to  evaporate  freely 
it  is  cooling,  and  tends  to  harden  the  skin  and  to  check  sweating. 
If  not  allowed  to  evaporate,  as  when  covered  with  flannel  or 
used  on  a  compress,  it  is  counterirritant,  producing  dilatation 
of  the  vessels,  with  warmth  and  reddening. 

Mucous  Membranes  and  Raw  Tissues. — To  these  it  is  irritant 
and  astringent,  for  it  abstracts  water  from  the  superficial  cells  and 
coagulates  their  protoplasm.  On  account  of  this,  strong  liquors 
for  internal  use  should  be  well  diluted.  Hertz  says  that  contact 
of  alcohol  with  any  part  of  the  digestive  canal  gives  rise  to  a 
sensation  of  heat. 

Alimentary  Tract. — A  chemic  substance  possessing  such 
striking  solvent  powers  and  affinities  requires  separate  considera- 
tion for — (a)  Its  effects  on  the  chemistry  of  the  contents  of  the 
stomach;  (b)  its  effects  on  the  stomach  wall;  and  (c)  its  effects 
on  the  stomach  functions.  It  is  well  to  remember  also  that  its 
local  action  depends  upon  the  degree  of  its  dilution,  rather  than 
upon  the  actual  amount  of  alcohol  involved. 

/.  Action  on  the  Chemistry  of  the  Stomach-contents. — Experi- 
ments in  vitro  indicate  that  50  per  cent,  alcoholic  liquids,  such  as 


322  PHARMACOLOGY   AND   THERAPEUTICS 

whisky  or  brandy  undiluted,  will  precipitate  the  proteins  of 
food,  will  to  some  extent  precipitate  pepsin,  and  will  check  the 
activity  of  the  digestive  process.  But  by  alcoholic  liquids  below 
20  per  cent,  in  strength  pepsin  in  solution  is  not  injured,  and  when 
the  proportion  of  alcohol  present  does  not  exceed  10  per  cent.,  or 
perhaps  even  15  per  cent.,  the  effect  upon  proteins  and  upon  the 
activity  of  the  digestive  ferments  in  the  test-tube  is  practically 
negative.  Solutions  up  to  2  per  cent,  in  strength  have  been 
shown  by  Chittenden,  Mendel,  and  Jackson  to  favor  the  activity 
of  pepsin  digestion. 

But  with  alcohol  there  is  a  great  difference  between  the 
actions  in  a  test-tube  and  those  in  the  stomach;  for  in  the  test- 
tube  the  alcoholic  strength  remains  the  same  throughout  the 
experiment,  and  the  products  of  digestion  are  not  removed, 
while  in  the  stomach  the  products  of  digestion  pass  away  and  the 
alcohol  strength  becomes  steadily  less,  owing  to  dilution  with 
gastric  juice  and  mucus  and  to  absorption  of  the  alcohol.  We 
are  safe  in  saying,  therefore,  that  in  the  human  alimentary  tract 
the  influence  of  moderate  quantities  of  properly  diluted  alcohol  upon 
the  chemic  processes  of  digestion  is  a  negligible  factor. 

With  the  alcoholic  drinks,  however — and  it  is  these  and  not 
pure  alcohol  that  are  in  common  use  both  in  therapeutics  and 
as  beverages — the  other  constituents  must  be  taken  into  con- 
sideration. The  volatile  constituents  of  wines  have  been  studied 
by  Krantwig  and  Vogel  (Binz),  and  found  to  have  a  pharma- 
cologic  action  similar  to  that  of  alcohol.  Their  proportion, 
however,  is  very  small.  Chittenden  and  Mendel  have  deter- 
mined that  the  distilled  liquors,  which  contain  the  same  or 
similar  volatile  substances,  exert  an  effect  upon  the  digestive 
chemistry  practically  proportional  to  the  amount  of  their  alco- 
hol. Hence  if  the  distilled  liquors  are  diluted  to  10  per  cent., 
they  have  no  harmful  effect  on  the  chemistry  of  digestion. 

But  Chittenden  and  Mendel  found  that  the  wines  and  malt 
liquors  tend  to  retard  pepsin  digestion,  even  when  their  alcohol 
is  much  below  the  harmful  percentage,  so  if  taken  in  considerable 
quantity  they  are  deleterious  to  digestion.  This  is  because  of 
their  organic  acids  and  colloidal  constituents,  and  not  because 
of  their  alcohol.  Red  wines,  because  of  their  tannic  acid,  which 
tends  to  precipitate  protein,  have  a  retarding  influence  beyond 
that  of  white  wine. 

2.  Action  on  the  Structures  of  the  Stomach-wall. — As  it  cannot 
evaporate  from  the  stomach,  alcohol  dilates  the  vessels  and  gives 
a  feeling  of  warmth  in  the  stomach.  Below  a  strength  of  10 
per  cent,  it  has  practically  no  other  effect  unless  taken  in  too 
large  quantities  to  be  absorbed  rapidly.  But  in  strength  above 


ALCOHOL  323 

50  per  cent.,  and,  to  many  stomachs,  in  much  weaker  dilution, 
it  is  powerfully  irritant  and  capable  of  causing  inflammatory 
changes.  Its  local  irritant  properties  depend  on  its  percentage 
dilution  rather  than  on  the  actual  amount  of  alcohol. 

j.  Action  on  the  Functions  of  the  Stomach. — The  chief  func- 
tions are  absorption,  motility,  and  secretion. 

(a)  Absorption. — Ordinary  amounts  of  alcohol  in  any  dilu- 
tion are  quickly  absorbed,  and  will  usually  have  disappeared 
from  the  stomach  in  less  than  half  an  hour  (Cushny  says  20  per 
cent,  absorbed  by  stomach  and  80  per  cent,  from  intestine.) 
But  during  a  meal  an  amount  of  alcohol  can  be  ingested  without 
systemic  effects  that,  if  taken  before  the  meal,  i.  e.,  on  an  empty 
stomach,  would  produce  distinct  feelings  or  manifestations  of 
intoxication.     This  is  a  fact  that  is  well  known  to  the  laity,  and 
the  difference  is  due  to  admixture  with  the  food  and  the  conse- 
quent retardation  of  absorption.     The  effect  of  alcohol  on  the 
absorption   of   other   substances,    such   as   digestive   products, 
water,  and  drugs,  is  usually  favorable,  unless  the  alcohol  is 
present  in  strength  great  enough  to  injure  the  cells  of  the  mucous 
membrane  or  to  produce  a  coating  of  thick  mucus,  or  to  act  as 
an  astringent,  i.  e.,  in  a  strength  above  about  20  per  cent. 

(b)  Motility. — Kast's  experiments  with  alcohol  up  to  20  per 
cent,  strength  indicated  increased  motility;  those  of  Gluzinski 
show  retarded  motility.     From  an  experimental  point  of  view, 
therefore,    the    effect    on    motility    remains    undecided.     Yet, 
clinically,  alcohol  seems  to  increase  the  motor  functions,  for 
solutions  containing  above  20  per  cent,  and  the  distilled  liquors, 
even  when  diluted  to  20  per  cent.,  are  prompt  and  powerful 
carminatives. 

(c)  Secretion. — /.   The   Secretion  of  Saliva   and   Mucus. — In 
the  mouth  these  are  increased  by  strong  alcohol,  as  with  other 
irritants,  the  resulting  secretion  being  for  protective  purposes. 

In  the  stomach,  also,  50  per  cent,  alcohol,  as  in  a  distilled 
liquor,  quickly  results  in  the  secretion  of  a  protecting  coat  of 
thick,  tenacious  mucus.  This  not  only  protects  the  mucous  mem- 
brane from  further  injury  by  the  alcohol,  but  by  retarding  absorp- 
tion serves  to  protect  the  liver  and  to  lessen  the  systemic  effects. 

2.  The  Secretion  of  Gastric  Juice. — We  are  able  to  divide  the 
action  of  alcohol  and  alcoholic  drinks  upon  this  secretion  into 
three  distinct  periods,  viz. : 

1.  The  period  of  excitation  of  the  taste-buds  or  olfactory 

nerves  to  produce  appetite. 

2.  The  period  during  which  the  alcohol  is  in  the  stomach. 

3.  The  period  after  absorption  while  the  alcohol  is  in  the 

circulating  blood. 


324  PHARMACOLOGY   AND   THERAPEUTICS 

First  Period. — Pawlow's  work  established  the  fact  that 
appetite  is  of  great  importance  in  the  production  of  the  first 
gastric  juice,  the  so-called  "appetite  juice,"  or  "psychic  gastric 
juice."  In  experiments  with  dogs  he  noticed  that  a  number  of 
substances,  for  example,  white  of  egg,  will  remain  absolutely 
undigested  if  placed  in  the  stomach  without  the  knowledge  of  the 
animal;  but  that  if  then  his  appetite  is  stimulated,  as  by  the 
sight  or  smell  of  food,  the  white  of  egg  is  soon  digested  because 
of  the  appearance  of  gastric  juice.  Hence  alcoholic  drinks  which 
promote  the  appetite,  whether  palatable  wines  or  bitter  malt 
liquors,  have  a  distinct  influence  in  the  production  of  the 
psychic  secretion  or  appetite  gastric  juice,  and  so  may  favor 
digestion. 

Second  Period. — Knowledge  of  the  effect  upon  the  secretion 
while  the  alcohol  is  in  the  stomach  was  obtained  from  experi- 
ments on  Pawlow  dogs  and  dogs  with  gastric  fistulae,  and  in 
addition  from  a  few  observations  made  upon  patients  with  gas- 
tric fistulae,  A  number  of  studies  were  made  by  Kast  upon  a 
girl  who  had  had  a  portion  of  the  esophagus  removed  and  a 
gastric  fistula  established.  The  work  of  Chittenden  and  Mendel 
was  done  on  dogs  with  gastric  fistulae,  a  regular  meal  being  al- 
lowed by  mouth,  and  measured  quantities  of  alcohol  being  put 
in  through  the  fistula.  From  these  observations  we  learn  that 
the  direct  influence  of  alcoholic  solutions  up  to  about  10  per  cent, 
in  strength  is  practically  none  at  all  upon  either  the  rate  or  the 
character  of  the  gastric  secretion;  while  from  amounts  above 
about  20  per  cent,  secretion  is  distinctly  retarded.  Between 
these  strengths  there  is  a  variable  influence.  There  is  some 
retardation  of  secretion  from  the  malt  beverages  because  of  their 
large  amount  of  extractive  matters,  and  from  the  red  wines 
because  of  their  tannic  acid;  but  the  retardation  in  these  cases  is 
not  due  to  the  alcohol. 

Third  Period. — When  alcohol  is  injected  into  the  blood  of  a 
dog,  a  flow  of  gastric  juice  results,  and  in  some  of  the  cases  at 
least  some  of  the  alcohol  is  excreted  into  the  stomach.  If 
alcohol  is  placed  in  the  rectum  or  in  any  part  of  the  intestine, 
absorption  is  also  followed  by  a  flow  of  gastric  juice.  And 
when  alcohol  is  placed  in  the  stomach  itself,  a  copious  flow  of 
gastric  juice,  perhaps  two  or  three  times  that  in  control  dogs, 
takes  place  after  all  the  alcohol  has  disappeared  from  the  stom- 
ach and  passed  into  the  blood.  In  all  these  cases  the  gastric 
juice  contains  hydrochloric  acid  out  of  all  proportion  to  the 
amount  of  pepsin  present.  Radzkowski  has  shown  that  the 
pepsin  of  this  juice  is  merely  that  already  transformed  from  the 
pepsinogen  in  the  glands,  and  that  no  new  pepsin  is  formed  as 


ALCOHOL  325 

the  result  of  the  absorbed  alcohol,  that  is  to  say,  only  the  chief 
cells  of  the  stomach  are  stimulated. 

The  secretion  following  administration  by  rectum  or  into  the 
blood  is  much  less  in  amount  than  that  following  stomach 
doses,  but  has  the  same  composition.  The  secretion  after 
absorption  lasts  until  practically  all  the  food  has  passed  the 
pylorus,  and  it  is  probable  that  alcohol  either  stimulates  the  acid- 
secreting  cells  directly,  or  else  causes  the  formation  of  a  hormone, 
which  is  absorbed  into  the  blood  and  stimulates  the  cells.  The 
effects  would  seem  to  be  of  the  same  nature  as  those  from  the 
hormone  known  as  gastric  secretin.  This  increase  in  the  secretion 
of  acid  and  in  the  amount  of  gastric  juice  after  the  absorption 
of  the  alcohol  is  of  practical  importance.  For  when  rectal  feeding 
in  an  irritant  stomach  condition,  such  as  ulcer,  is  adopted  for  the 
purpose  of  saving  the  stomach  from  irritation,  it  is  advisable 
to  omit  alcohol  from  the  enema.  In  old  alcoholics  the  stomach 
is  usually  the  site  of  a  chronic  inflammation. 

Summary  of  the  Effects  upon  the  Stomach  and  its  Functions : 

1.  In  so  far  as  they  stimulate  the  appetite,  alcoholic  beverages 

induce  a  psychic  secretion  of  gastric  juice. 

2.  While  in  the  stomach,  alcohol  in  10  per  cent,  dilution  has 

little  if  any  effect  upon  the  digestive  chemistry,  the  motor 
activity,  or  the  secretion;  the  wines  and  malt  liquors  tend 
to  retard  secretion  and  the  digestive  chemistry. 

3.  While  it  remains  in  the  stomach,  alcohol  up  to  20  per  cent. 

in  strength  promotes  absorption  of  other  substances. 

4.  After   absorption   from    the   stomach   alcohol   induces   a 

copious  flow  of  gastric  juice  rich  in  hydrochloric  acid  and 
poor  in,  or  devoid  of,  pepsin;  the  same  qualitative  result 
being  obtained,  though  less  in  quantity,  when  alcohol 
is  given  by  rectum  or  injected  directly  into  the  blood. 

5.  Strong  liquors  are  carminative,  but  in  the  empty  stom- 

ach irritate  and  induce  a  secretion  of  thick,  tenacious 
mucus. 

6.  Long-continued  drinking  of  strong  liquors  tends  to  produce 

a  chronic  gastritis. 

Taken  by  mouth,  in  moderation  and  properly  diluted,  alco- 
holic drinks  tend  to  improve  the  appetite,  to  give  a  feeling  of 
warmth  and  comfort  in  the  stomach,  and  to  promote  the  secre- 
tory and  absorptive  functions.  In  conditions  of  hyperchlor- 
hydria,  hypersecretion,  or  ulcer  of  the  stomach,  they  tend  to  be 
harmful.  Ordinary  amounts  of  even  strong  liquors  taken  at 
meals  are  quickly  brought  down  to  proper  dilution  by  admixture 
with  the  contents  of  the  stomach,  and  this  admixture  with  food 
retards  their  absorption  and  their  systemic  activity. 


326  PHARMACOLOGY   AND   THERAPEUTICS 

Intestines. — After  alcohol  in  moderate  quantities  any  amount 
that  may  be  carried  through  the  pylorus  is  probably  too  dilute 
to  have  any  local  effect  in  the  intestine.  After  excessive  drink- 
ing some  of  it  reaches  the  duodenum  and  acts  there  as  an  irritant. 
A  factor  of  influence  upon  the  intestine  may  be  a  delay  in  the 
passage  of  food  from  the  stomach  as  a  result  of  the  induced 
hyperchlorhydria.  (Brandy  has  a  reputation  as  an  intestinal 
astringent,  and  is  used  in  small  amounts  for  diarrhea.) 

Pancreas. — The  amount  of  pancreatic  secretion  is  increased 
even  up  to  five  times  the  normal,  whether  the  alcohol  is  placed 
in  the  stomach,  the  small  intestine,  the  colon,  or  the  rectum. 
It  may  be  that  this  also  is  due  to  increased  formation  of  the 
secretin. 

Of  the  ferments,  experiments  in  vitro  have  demonstrated  that 
alcohol  of  5  per  cent,  strength  is  completely  inhibitory  to  the 
action  of  trypsin  and  amylopsin,  the  proteolytic  and  starch- 
digesting  ferments  of  the  pancreatic  juice;  while  in  any  strength 
up  to  90  per  cent,  it  distinctly  favors  the  action  of  steapsin,  the 
fat-splitting  ferment.  When  added  to  pancreatic  juice  which  is 
obtained  from  a  fistula,  alcohol  markedly  increases  the  lipolytic 
power  of  the  secretion;  so  it  would  seem  to  have  the  property 
of  changing  the  proferment  into  the  active  ferment,  steapsin. 
After  ordinary  amounts  this  action  upon  the  ferments  does  not 
take  place,  as  little  of  the  alcohol  reaches  the  intestinal  contents. 
After  very  large  amounts  such  an  action  may  influence  the 
intestinal  digestive  process. 

Liver. — From  the  stomach  and  duodenum  the  absorbed 
alcohol  passes  by  the  portal  circulation  directly  to  the  liver. 
Moderate  amounts  are  sufficiently  diluted  by  the  portal  blood. 
Large  amounts,  as  in  excessive  drinking,  surcharge  the  portal 
blood  with  alcohol.  This  attacks  the  hepatic  parenchyma,  as 
shown  by  the  presence  of  albumin  and  epithelial  cylinders  in  the 
bile,  and  swelling  of  the  liver,  with  more  or  less  fatty  degeneration. 
In  other  words,  it  produces  an  acute  hepatitis.  This  usually 
disappears  in  a  few  days  if  no  more  alcohol  is  drunk;  but  a  single 
excessive  dose  does  vastly  more  harm  to  the  liver  than  the  same 
amount  of  liquor  taken  a  little  at  a  time. 

Good-sized  doses  of  liquor,  frequently  repeated  during  many 
years,  tend  to  establish  permanent  changes  in  the  liver — either 
fatty  degeneration  or  connective-tissue  invasion  (cirrhosis),  or 
both. 

It  is  a  well-known  fact  that  the  drinking  of  large  quantities 
of  alcohol  for  years  is  a  regular  prelude  to  the  appearance  of 
cirrhosis  of  the  liver.  A  number  of  children  also  who  have  been 
given  beer  or  wine  have  developed  cirrhosis  of  the  liver.  There- 


ALCOHOL  327 

fore  there  is  a  close  relation  between  cirrhosis  and  alcohol.  Yet 
in  animals,  though  the  continued  administration  of  alcohol 
readily  produces  a  fatty  liver,  even  in  starved  dogs  (prevented  by 
sugar — Von  Noorden),  almost  all  investigators,  Strassmann, 
Afanassiew,  von  Kahlden,  etc.,  have  been  unable  to  produce 
typical  cirrhosis  even  by  prolonged  administration.  I  have 
reports  of  true  cirrhosis  being  so  produced  in  animals  in  only  very 
few  cases.  It  seems,  then,  that  it  takes  years  of  excessive  alcohol- 
ism before  any  extensive  connective-tissue  changes  can  be  de- 
tected, and  it  is  quite  probable  that  the  production  of  cirrhosis 
of  the  liver  requires  more  than  alcohol.  (See  "The  Pathologic 
Effects  on  Organs,"  page  350.) 

The  Bile.—  Alcohol  is  excreted  in  the  bile  only  after  large  doses, 
and  the  amount  excreted  is  quickly  reabsorbed  from  the  intes- 
tine. The  quantity  of  bile,  both  liquid  and  solid  constituents, 
may  be  much  increased.  Salant's  experiments  showed  that 
when  alcohol  was  given  by  stomach  the  bile  increased  50  to  365 
per  cent.;  when  alcohol  was  placed  in  the  intestine  the  bile 
increased  80  to  140  per  cent.,  and  the  solid  constituents  were 
increased.  This  would  be  the  effect  expected  coincidentally 
with  the  increase  of  pancreatic  secretion  (Starling)  if  the  alcohol, 
as  we  suggested  before,  results  in  increased  production  of  secretin. 
It  seems  especially  probable  that  this  is  the  case,  because  alcohol 
itself,  under  ordinary  circumstances,  does  not  reach  the  intestines 
in  strength  sufficient  to  have  any  effect,  either  direct  or  reflex. 
Salant  reported,  however,  that  alcohol  injected  into  the  blood 
caused  a  reduction  in  the  secretion  of  bile.  In  addition  to  these 
effects  excessive  amounts  may  hasten  the  disappearance  of 
glycogen  from  the  liver,  with  tendency  to  increase  fat  and  lessen 
the  oxidative  processes  of  the  liver,  as  shown  by  the  appearance 
of  more  uric  acid  and  less  urea  in  the  urine,  and  by  an  increase 
of  the  poisonous  symptoms  in  indolic  auto-intoxication.  Several 
researches  go  to  show  that  sugars  tend  to  lessen  these  effects. 

Absorption  is  rapid  from  stomach  or  intestines.  It  is  retarded 
by  fats,  as  milk,  cream,  or  oil  emulsions  (Jacoby). 

Nervous  System. — As  alcohol  is  an  ethyl  compound,  C2H5OH, 
with  a  close  relation  to  ether,  (CaHs^O,  it  is  not  surprising  to 
find  that  the  alcohol  effect  upon  the  central  nervous  system  is 
the  same  in  kind  as  that  of  ether,  though  modified  by  its  dimin- 
ished volatility  and  slower  action.  It  depresses  first  the  highest 
cerebral  centers  of  all,  the  intellectual  centers,  then  the  lower 
cerebral  centers  (motor,  emotional,  animal),  then  the  cerebellum, 
then  the  spinal  cord,  and  finally  the  vital  centers  of  the  medulla. 
There  is  probably  a  primary  stimulation  from  protoplasmic 
irritation,  but  this  is  momentary,  and  alcohol  cannot  be  con- 


328  PHARMACOLOGY   AND   THERAPEUTICS 

sidered  in  any  sense  a  cerebral  stimulant.  It  is  a  true  narcotic, 
and  it  stands  in  the  narcotic  series  between  the  general  anes- 
thetics, which  are  very  volatile,  very  prompt,  and  transitory  in 
their  action,  and  very  powerful  in  their  effects,  and  the  hypnotics, 
of  which  a  dose  must  be  able  to  maintain  a  mild  degree  of  narcosis 
for  several  hours. 

The  symptoms  of  acute  alcohol  poisoning  or  drunkenness  are 
only  too  familiar.  They  are  readily  explainable  as  the  effects 
of  a  narcotic  drug.  Normally,  our  animal  tendencies  are  under 
the  restraint  of  the  highest  brain  centers — those  through  whose 
activity  are  exerted  will,  self-control,  reasoning  power,  judg- 
ment, etc.  By  these  we  hold  ourselves  to  certain  standards  of 
conduct,  and  keep  in  proper  check  the  more  animal  parts  of  our 
natures.  We  weigh  facts  and  estimate  the  consequences  of  our 
acts;  we  are  thoughtful  of  our  relations  to  others,  and  mind  what 
others  may  think  of  us. 

Under  alcohol  these  highest  faculties  are  depressed,  and  there 
is  a  certain  degree  of  freedom  from  restraint,  i.  e.,  "there  is  a 
breaking  of  the  fetters  which  keep  our  animal  natures  within 
bounds"  (Dubois).  The  result  is  the  failure  of  judgment,  the 
inability  to  appreciate  the  consequences  of  one's  acts,  great  con- 
fidence in  one's  mental  and  physical  powers,  and  a  lack  of  care 
about  the  kind  of  impression  made  upon  one's  neighbors.  Speech 
is  freer,  because  of  less  thinking  before  speaking  and  less  concern 
about  the  best  word  to  say  or  the  best  way  in  which  to  voice 
one's  thoughts.  Confidence  in  one's  powers  extends  both  to  the 
physical  and  to  the  mental,  as  seen  in  one's  willingness  or  anxiety 
to  fight  a  man  of  twice  one's  strength,  and  in  the  belief  of  a 
writer  that  he  is  doing  splendid  work,  though  at  a  later  perusal 
he  finds  it  trashy  and  full  of  errors. 

A  great  many  experiments  have  been  performed  to  determine 
the  exact  effect  upon  the  faculties  of  small  quantities  of  alcohol, 
and  while  some  of  them  show  primary  stimulation,  depression 
is  the  rule.  A  study  of  type-setters,  for  example,  has  shown 
that  they  make  more  errors  even  under  very  small  amounts  of 
alcohol;  pianists  strike  more  wrong  notes;  sight  and  hearing  are 
less  keen;  the  sense  of  touch  is  impaired  (as  measured  by  the 
esthesiometer).  Kraepelin  found  that  the  perception  of  a  word 
or  letter  flashed  before  the  eye  was  slightly  less  rapid,  but  that  a 
motor  response  was  more  rapid;  and  this  might  be  because  of 
freedom  of  the  motor  areas  from  the  inhibition  required  in  judg- 
ment. In  some  persons  some  of  the  depression  persisted  for  from 
twelve  to  twenty-four  hours.  In  some  there  was  no  depression 
at  all,  even  from  100  c.c.  of  alcohol,  which  would  be  the  amount 
in  a  tumblerful  of  whisky.  Jacoby  found  that  alcohol  made  a 


ALCOHOL  329 

keener  perception  of  differences  of  weight,  but  thought  this  due 
to  slower  (more  deliberate)  cerebration.  Some  observers  have 
noted  a  brief  period  of  true  stimulation  of  the  perceptive  faculties 
before  the  general  depression  supervenes.  Many  have  thought 
that  the  quicker  action  in  response  to  a  stimulus  was  due  to 
primary  freeing  of  the  motor  functions  from  inhibition.  It 
has  been  shown  that  from  comparatively  small  amounts  marks- 
manship is  impaired  with  rifle  and  pistol;  and  Totterman  in  a 
needle- threading  test  found  that  eleven  hours  after  25  c.c.  fewer 
needles  could  be  threaded  in  a  given  time. 

With  doses  of  i  and  i^  ounces  (30  and  45  c.c.)  Dodge  and 
Benedict,  from  an  extensive  study  of  the  psychologic  effects 
of  alcohol,  at  the  Carnegie  Nutrition  Laboratory,  find  "a  gen- 
erally decreased  irritability  of  many  related  neuromuscular 
processes,  regularly  accompanied  by  relative  acceleration  of  the 
pulse-rate.  These  two  facts  are  clear  indications  of  decreased 
organic  efficiency." 

Alcohol,  then,  is  an  intellectual  depressant,  i.  e.,  a  narcotic, 
and  it  is  a  direct  antagonist  of  caffeine.  Yet  on  some  particular 
occasions,  or  in  special  kinds  of  work,  the  peculiar  narcotic  effects 
of  alcohol,  if  not  taken  to  excess,  may  actually  favor  better  work, 
for  example — (a)  Where  nervousness,  or  embarrassment,  or  anx- 
iety cause  too  great  inhibition  and  prevent  unembarrassed  think- 
ing, e.  g.,  one  who  is  to  speak  in  public  may  increase  his  confidence, 
lessen  his  self-consciousness,  and  set  free  his  thoughts,  so  that  he 
can  speak  without  embarrassment,  (b)  When  the  writer  of  imag- 
inative or  emotional  literature  or  poetry  is  unable  to  get  himself 
into  the  imaginative  state;  a  dose  of  whisky  may  set  free  his 
imaginative  powers,  so  that  he  can  outline  his  story,  any  errors 
of  grammar  or  construction  being  corrected  later,  (c)  When  a 
musician  is  unable  to  reach  the  emotional  state  necessary  to 
enthuse  his  hearers,  he  may  find  himself  able  to  do  so  after  a 
drink  of  whisky,  for  though  he  may  strike  a  number  of  wrong 
notes,  he  puts  life  into  his  music  and  thrills  his  audience.  These 
are  not  cases  of  intellectual  stimulation,  but  intellectual  depres- 
sion. Though  these  things  are  true  in  particular  instances,  I 
would  caution  against  depending  on  any  such  aid,  for  it  is  impos- 
sible to  predict  the  dose  that  will  just  give  the  desired  assistance. 
Too  much  alcohol  spoils  everything,  for  the  inferiority  of  work 
produced  is  not  realized  by  the  drinker.  Work  requiring  con- 
centration; deduction,  and  keenness  of  judgment,  such  as  scien- 
tific writing  or  investigation,  cannot  be  done  so  well  under  the 
influence  of  even  small  amounts  of  alcohol. 

Sexuality. — From  depression  of  the  cerebrum  the  sexual  de- 
sires are  under  much  less  restraint  than  normal,  and  Havelock 


330  PHARMACOLOGY  AND  THERAPEUTICS 

Ellis  rightly  says:  "It  is  obvious  that  those  who  wish  to  cultivate 
a  strict  chastity  of  thought  and  feeling  would  do  well  to  avoid 
alcohol  altogether,  or  to  use  it  in  its  lightest  forms  and  in  modera- 
tion." If  much  alcohol  is  taken,  the  sexual  powers  are  impaired 
from  depression  of  the  spinal  cord,  though  the  animal  desire  may 
still  be  present.  In  chronic  alcoholics  sexuality  is  not  infre- 
quently abolished;  indeed,  atrophy  of  the  testicles  is  frequent. 

Hypnotic  Action. — Other  things  being  equal,  alcohol,  taken 
without  exhilarating  company,  tends  to  promote  drowsiness  and 
sleep.  Hence  the  use  of  beer,  ale,  or  the  hot  toddy  at  bedtime. 

Stupor. — If  much  alcohol  is  taken  in  a  short  time  the  intoxica- 
tion (exhilaration)  stage  is  followed  by  bodily  inactivity,  mental 
dulness,  and  inattention.  There  is  also  ataxia  from  loss  of 
muscular  sense,  so  that  it  is  difficult  to  button  one's  coat  or  to 
walk  in  a  straight  line  or  to  tell  just  where  one's  legs  are.  The 
gait  is  staggering,  either  because  of  the  ataxia  or  from  cerebellar 
depression,  and  the  speech  is  thick.  During  the  stages  of  intox- 
ication and  stupor  there  is  some  general  anesthesia  from  depres- 
sion of  the  sensory  centers,  so  that  the  alcoholic  may  injure 
himself  without  pain,  as  when  he  burns  his  fingers  with  a  cigar  or 
falls  and  breaks  a  limb.  There  is  also  some  muscular  relaxation 
from  depression  of  the  reflexes,  and  this  accounts  for  the  notice- 
able escape  from  fractures  in  drunken  falls.  As  with  ether,  the 
sensory  centers  are  affected  before  the  motor,  and  there  may  be 
early  impairment  of  feeling  in  the  hands  and  feet;  but  the  loss 
of  muscular  control  may  not  be  noticed  until  the  victim  attempts 
to  walk.  After  this  stage  the  patient  may  pass  into  an  anes- 
thetic, stuporous  sleep,  with  slow  and  perhaps  stertorous  breath- 
ing; and  he  may  even  go  on  to  coma,  collapse,  and  death.  Previ- 
ous to  the  employment  of  ether  and  chloroform  as  anesthetics, 
whisky  in  intoxicating  quantities  was  frequently  administered  as 
a  preliminary  to  major  operations. 

It  is  observed  that  when  liquor  is  taken  without  exhilarating 
surroundings  and  company,  as  by  an  invalid  in  bed,  the  drowsy 
or  quiet  stage  supervenes  without  much  preliminary  exhilaration. 

Them  politically,  the  only  desired  effect  upon  the  cerebrum  is 
the  narcotic  one  of  quieting  the  nervous  system,  as  in  fevers  or 
emotional  shock  or  insomnia. 

Cerebellum. — In  the  intoxication  there  is  incoordination,  as 
shown  by  staggering  gait,  inability  to  use  the  hands  with  dex- 
terity, and  mixed  or  incoherent  speech.  These  things  may, 
however,  as  mentioned  above,  be  due  to  other  depressions  than 
that  of  the  cerebellum. 

Spinal  Cord. — The  reflexes  are  depressed,  and  the  tone  of 
muscle  and  the  response  to  external  stimuli  are  much  lessened. 


ALCOHOL  331 

Muscular  relaxation  has  been  spoken  of.  The  bladder  reflex  may 
fail,  so  that  urine  accumulation  distends  the  bladder.  This  may 
go  on  to  a  dangerous  degree,  and  catheterization  become  neces- 
sary. The  sexual  powers  fail. 

Peripheral  Nerves. — There  is  some  depression  of  the  nerves 
and  nerve-endings,  including  the  nerves  of  muscular  sense, 
though  the  main  factor  in  the  anesthesia  is  central  depression. 
In  the  excessive  and  continued  use  of  alcohol  its  affinity  for  the 
nerves  is  shown  in  the  frequency  with  which  it  produces  a  neuritis. 

To  sum  up  the  action  of  alcohol  as  a  narcotic  we  might  say 
that  it  produces  practically  the  same  stages  as  ether,  but  that  the 
stages  are  modified  by  the  much  slower  rate  at  which  the  narcosis 
is  produced;  and  that  as  alcohol  is  usually  taken  by  stomach, 
rather  than  by  inhalation,  any  irritant  effects  manifest  them- 
selves upon  the  stomach  and  liver  instead  of  upon  the  nose, 
throat,  and  bronchi. 

The  stages  of  alcohol  narcosis  are : 

1.  Stage  of  blunted  perceptive  and  intellectual  faculties. 

2.  Intoxication — a  much  prolonged  stage. 

3.  Stupor — general  dulness  and  inattention  leading  to  stupor- 
ous  sleep. 

4.  Coma  (serious),  leading  to  collapse  and  death. 

The  apparent  stimulating  effects  of  alcohol  are  dependent 
essentially  upon  the  .following  factors: 

1.  The  local  irritation — this  results  in  true  reflex  stimulation 
of  the  circulation,  but  of  only  short  duration.     The  less  the  dilu- 
tion, the  greater  is  the  reflex  effect. 

2.  The  feeling  of  warmth — due  to  general  dilatation  of  the 
skin  vessels. 

3.  The  early  narcotic  effect  of  depression  of  the  higher  centers, 
with  freedom  of  the  imaginative  and  emotional,  and  increase  of 
confidence  in  one's  physical  and  mental  powers. 

4.  The  food  value — which  is  a  striking  factor  only  in  condi- 
tions of  debility  and  exhaustion. 

5.  In  company,  the  effect  of  increased  sociability  and  exhila- 
rating environment. 

Food  Value. — A  food  may  be  defined  as  a  substance  whose 
dominant-  property  in  the  body  is  to  build  up  the  tissues  or  to 
yield  energy.  Protein  is  our  reliance  for  the  building  or  recon- 
struction of  tissue;  carbohydrates  and  fats  are  restricted  to  fur- 
nishing energy.  It  is  evident,  from  its  chemical  constitution, 
that  alcohol  has  no  power  to  build  tissue.  We  might  inquire, 
then,  into  its  value  in  the  production  of  energy. 

To  What  Extent  Can  Alcohol  be  Oxidized  in  the  Body? — God- 
dard  administered  16  gm.  of  absolute  alcohol,  properly  diluted, 


332  PHARMACOLOGY   AND   THERAPEUTICS 

to  a  fasting  dog  weighing  12.4  kilos  (about  25  pounds),  and  found 
that  all  the  alcohol  had  disappeared  in  five  and  one-half  hours, 
and  that  only  about  5  per  cent,  of  it  had  been  recovered,  some 
in  the  breath  and  some  in  the  urine,  i.  e.,  95  per  cent,  had  been 
completely  oxidized.  If  humans  oxidize  alcohol  at  the  same  rate, 
a  man  of  160  pounds  could  dispose  of — i.  e.,  burn  up  and  utilize 
for  energy — 6  ounces  of  whisky  given  at  one  dose — about  three- 
fourths  of  a  tumblerful,  or  enough  to  produce  drunkenness.  To 
test  this  Atwater  and  Benedict  treated  healthy  men  with  six 
i -ounce  doses  given  with  food  at  intervals  during  the  day.  It 
was  completely  oxidized,  except  for  the  small  amount  of  1.9  per 
cent,  that  was  recovered  from  the  breath  and  urine.  Alcohol 
in  any  ordinary  amounts  is,  therefore,  practically  completely 
burned  up  by  the  body.  In  Goddard's  experiments  larger 
amounts  than  mentioned  above  resulted  in  the  appearance  in 
the  breath  and  urine  of  aldehyde  and  other  incompletely  oxidized 
products  of  alcohol. 

Can  Alcohol  Directly  Replace  Fats  in  the  Food? — Atwater  and 
Benedict  placed  a  man  on  a  fixed  diet  of  mixed  character.  Dur- 
ing thirteen  days  of  resting  he  increased  in  weight  an  average  of 
33.7  gm.  daily,  i.  e.,  stored  up  that  much  surplus.  When  for 
ten  days  72  gm.  alcohol,  as  in  6  ounces  of  whisky  or  a  quart  of 
claret,  was  given  each  day,  and  its  equivalent  in  fat  deducted 
from  the  daily  dietary,  the  average  gain  was  34.1  gm.  daily.  It 
was  not  alcohol  that  was  stored  up,  but  fat,  the  alcohol  being 
burned  up  first  to  supply  the  energy,  and  a  corresponding  amount 
of  fat  being  spared  to  be  stored  up.  There  was  no  increase  in 
the  intake  of  oxygen  or  the  output  of  CO2  other  than  that  normally 
following  the  ingestion  of  food. 

These  same  experimenters,  Atwater  and  Benedict,  also 
studied  the  metabolism  of  a  man  who  was  fed  for  alternating 
periods  of  five  days  on  a  definite  mixed  diet,  and  on  the  same  diet 
but  with  72  gm.  of  alcohol  replacing  an  isocaloric  amount  of  fat 
in  the  daily  allowance.  During  the  first  two  periods  of  five  days 
the  man  was  at  rest,  and  during  two  other  five-day  periods  he 
was  at*  hard  work.  They  found  that,  both  during  the  rest 
periods  and  the  hard-work  periods,  the  total  metabolism  was 
practically  the  same  on  the  alcohol  dietary  as  on  that  containing 
fat.  Therefore  alcohol  supplied  the  energy  for  rest  or  for  work 
just  as  well  as  fat  did,  and  prevented  drawing  upon  the  tissues. 

We  might  refer  also  to  the  experiments  of  Hellsten  and  of 
Schnyder  and  Dubois,  and  of  the  German  government  (see 
below),  which  established  the  energy-producing  value  of  alcohol 
when  the  regular  food-supply  was  deficient.  The  experiments 
of  Rosemann  (1901)  on  himself  over  a  period  of  thirty-seven  days,. 


ALCOHOL  333 

and  of  Neumann  (1901)  on  dogs  in  two  periods  of  twenty-five 
and  thirty-six  days,  give  also  some  exact  data  as  to  the  ability  of 
alcohol  to  prevent  tissue  waste  and  to  replace  fat  in  the  dietary. 
One  of  Neumann's  experiments  was  as  follows:  For  five  days  he 
kept  dogs  in  nitrogen  equilibrium  (that  is,  on  a  mixed  diet  whose 
daily  nitrogen  was  the  same  in  amount  as  the  daily  excretion  of 
N).  He  then  for  four  days  gave  the  same  diet,  but  with  half  its 
fat  omitted;  the  nitrogen  excretion  increased,  showing  that  there 
was  more  protein  destruction,  i.  e.,  the  proteins  were  being  drawn 
upon  to  supply  the  energy  that  the  fat  had  supplied.  Then 
alcohol,  in  amount  chemically  equivalent  to  the  omitted  fat, 
was  added  to  the  food,  and  the  nitrogen  equilibrium  again  became 
established.  Therefore  alcohol  was  able  to  spare  the  proteins 
in  the  same  way  as  the  fat.  But  Neumann  went  further,  and 
not  only  gave  the  alcohol,  but  also  replaced  the  omitted  fat,  and 
the  nitrogen  excreted  became  less  than  that  ingested,  i.  e.,  there 
was  less  protein  destruction  than  with  either  alcohol  or  fat  alone, 
and  protein  was  being  stored  up,  so  that  alcohol  performed  the 
function  of  fat  in  sparing  protein  even  when  the  fat  in  the  food 
was  sufficient.  Lastly,  Neumann  omitted  both  the  fat  and  the 
alcohol,  and  the  nitrogen  excretion  again  greatly  exceeded  that 
taken  in  with  the  food,  that  is,  there  was  excessive  protein  de- 
struction. We  might  sum  up  the  teachings  of  these  experiments 
as  follows:  When  fat  in  the  food  is  deficient,  alcohol  can  entirely 
compensate  for  the  deficiency,  at  least  for  a  short  period;  it  yields 
the  energy  that  fat  would  yield,  and  so  spares  protein  and  prevents 
tissue  waste.  When  alcohol  and  fat  are  administered  together  in 
quantities  above  the  needs  of  the  body,  the  alcohol  is  the  more  easily 
utilized  to  supply  energy,  so  that  the  fat  is  spared  and  stored  up  in 
the  body. 

(In  metabolism  experiments  with  alcohol  it  has  been  found 
that  there  is  usually  a  loss  in  protein  for  the  first  three  or  four 
days  until  tolerance  is  established;  but  if  the  alcohol  is  begun  in 
very  small  doses,  the  primary  protein  destruction  does  not  occur; 
and  in  those  accustomed  to  alcohol,  even  larger  quantities  of 
alcoholic  drinks  result  in  no  primary  nitrogen  loss,  even  in  fever. 
— Ott.) 

Can  Alcohol  Directly  Replace  Carbohydrates  in  the  Food?— 
To  test,  this,  Atwater  and  Benedict  studied  the  metabolism  of  a 
man  at  rest  during  five-day  periods.  During  the  first  period  he 
was  on  a  fixed  diet,  without  sugar,  representing  2290  absorbable 
calories.  He  gained  very  slightly  in  weight,  the  daily  calories 
of  metabolism  being  2176,  and  the  calories  of  retention  being  77. 
During  the  second  period  he  took  the  same  diet  plus  72  gm.  of 
alcohol  (500  calories),  and  gained  more  in  weight;  the  calories  of 


334 


PHARMACOLOGY   AND   THERAPEUTICS 


metabolism  being  2258  and  those  of  retention  589.  During  the 
third  period  he  took  the  same  diet  with  the  exclusion  of  the 
alcohol,  and  the  substitution  therefor  of  130  gm.  of  sugar  (515 
calories);  the  calories  of  metabolism  being  2272  and  those  of 
retention  562,  practically  the  same  as  with  the  alcohol.  There 
was  no  essential  difference  in  the  intake  of  oxygen  or  output  of 
carbon  dioxide,  except  that  associated  with  the  taking  of  any 
food. 


ABSORBABLE 
CALORIES 

CALORIES  OP 
METABOLISM 

CALORIES  or 
RETENTION  is 
WEIGHT 

Fixed  diet  

2  200 

2176 

77 

Fixed  diet  +  72  gm.  alcohol. 
Fixed  diet  +  130  gm.  sugar  .  . 

2290  +  500 
2290  +  515 

2258 
2272 

589 
562 

Rosenfeld  (1900),  in  an  eleven-day  experiment  with  a  nitrogen 
equilibrium  diet,  found  that  120  gm.  of  alcohol  caused  a  nitrogen 
saving  of  17  per  cent.,  and  that  a  corresponding  sparing  of 
nitrogen  occurred  from  equivalent  amounts  of  cane-sugar.  Durig 
(1913)  gave  abundance  of  sugar  with  and  without  alcohol,  and 
found  that,  despite  the  surfeit  of  sugar,  the  alcohol  was  the  first 
to  be  burned  for  the  liberation  of  energy.  Hammett  found  no 
change  in  the  nitrogen  partition  of  the  urine  when  alcohol  was 
substituted  for  sugar  in  a  mixed  diet.  From  these  data  we  may 
conclude  that  alcohol  in  moderate  quantities  given  with  a  mixed 
diet  can  replace  equivalent  amounts  of  carbohydrates  in  the  food,  at 
least  for  a  short  period.  It  is  noteworthy,  however,  that  Higgins, 
Peabody,  and  Fitz  found  alcohol  completely  incapable  of  checking 
an  acidosis  brought  on  by  carbohydrate  starvation,  though  the 
acidosis  promptly  disappeared  on  the  administration  of  carbo- 
hydrates. 

The  caloric  value  of  alcohol  is  7.1  calories  per  gram — i.  e., 
one  gram  of  alcohol  is  equivalent  in  energy-producing  power  to 
1.75  grams  of  carbohydrate,  or  0.77  gram  of  fat. 

The  beer-drinkers'  adipose  is  well  known.  In  the  malt 
liquors  there  is  much  nutritive  albuminous  and  carbohydrate 
material  in  addition  to  the  alcohol.  A  liter  of  beer  containing 
5  per  cent,  by  volume  of  alcohol  would  contain  50  c.c.  (40  gm.) 
of  alcohol,  representing  284  calories,  and  extractive  matter 
representing  from  200  to  275  calories,  according  to  its  "body." 
Hence  a  liter  of  beer  may  furnish  500  calories,  or  as  much  as  one- 
sixth  of  the  necessary  food  requirements  of  a  man  at  work. 

An  interesting  theory,  held  by  some  biologists,  is  that  the 


ALCOHOL  335 

pancreas,  by  means  of  a  ferment,  converts  carbohydrates  into 
alcohol,  which  is  then  oxidized  in  the  tissues  to  produce  energy. 
Fat  is  deposited  in  the  tissues  as  the  result  of  an  intracellular 
synthesis  of  alcohol  and  a  fatty  acid. 

Muscle,  Power,  and  Endurance. — Lee  and  Salant  found  that 
in  frogs,  while  weak  alcohol  has  little  effect  on  striated  muscle, 
10  per  cent,  alcohol  is  a  direct  stimulant.  In  25  experiments  on 
the  contraction  of  a  curarized  frog's  gastrocnemius  the  average 
increase  in  the  number  of  contractions  in  the  alcoholized  frog 
was  59.5  per  cent.,  and  the  average  increase  of  total  work  done 
by  the  muscle  was  40.4  per  cent.  Their  conclusion  was  that 
alcohol  in  moderate  quantities  results  in  quicker  contraction  and 
quicker  relaxation  of  the  muscle,  with  a  larger  number  of  con- 
tractions, increased  amount  of  work  in  a  given  time,  and  delay 
of  fatigue.  In  these  cases,  of  course,  there  was  no  supply  of 
nutritive  material  and  the  alcohol  may  have  served  as  food. 

Human  ergographic  and  dynamometric  experiments  indicate 
that  small  quantities  increase  the  power  for  muscular  work  for 
a  short  time,  but  that  fatigue  sets  in  more  early. 

Hellsten  (1904)  showed  that  10  gm.  of  alcohol  given  to  a  non- 
drinker  increased  the  muscular  power  for  the  first  half-hour  up  to 
9  per  cent.,  the  best  work  being  done  during  the  second  period  of 
fifteen  minutes;  in  the  third  period  of  fifteen  minutes  the  mus- 
cular power  decreased  to  6  per  cent,  below  normal.  After  mod- 
erate fatigue  the  primary  increase  after  alcohol  was  more  notice- 
able. From  his  experiments  he  concluded  that  there  was  some 
primary  stimulation  either  of  the  motor  centers  or  muscle,  and 
that  in  fatigue,  or  when  nutritive  material  was  lacking,  the  effect 
of  the  alcohol  as  food  enhanced  the  stimulation.  The  subse- 
quent decrease  in  muscular  power  is  essentially  due  to  the  depres- 
sion of  the  motor  centers  of  brain  and  cord. 

Schnyder  and  Dubois  (1903)  compared  alcohol  with  tropon 
(a  protein  food).  From  over  400  ergograph  experiments  they 
concluded  that  alcohol  in  small  quantities  has  a  favorable  action 
on  muscular  power  when  it  is  taken  by  a  fasting  person  who  has 
to  some  degree  exhausted  his  reserves  by  active  work.  But  that 
because  of  the  central  depressant  effect  the  increase  in  muscular 
power  is  below  that  from  an  ordinary  food  substance  of  the  same 
caloric  value;  and  that,  if  the  individual  has  already  an  adequate 
food-supply,  the  late  depression  of  muscular  power  may  be  the 
only  manifestation  of  the  alcohol. 

It  is  evident  from  such  experiments  that  any  good  effects  on 
muscle  and  work  depend  not  on  stimulation,  but  on  nutrition. 

Endurance. — Tests  with  soldiers  made  by  Leistenstorfer  over 
a  number  of  days,  have  shown  that,  in  a  regiment  on  the  march, 


336  PHARMACOLOGY   AND   THERAPEUTICS 

provided  that  all  were  well  fed,  those  companies  which  received 
no  alcohol  during  the  day  were  able  to  march  further  or  were  in 
better  condition  at  the  end  of  the  day  than  the  companies  which 
received  alcohol.  If  they  were  underfed,  those  receiving  alcohol 
in  the  ration  could  endure  the  most. 

Zuntz  and  Schumberg  made  a  study  on  the  temperature  of 
marching  soldiers,  and  found  that  while  normally  they  could 
carry  an  average  load  of  22  kilograms  and  march  15  to  20  kilo- 
meters without  noticeable  rise  in  body-temperature,  yet  from  the 
same  work,  after  a  drinking-bout,  the  temperature  rose  to  from 
102.7°  F.  (39.3°  C.)  to  105°  F.  (40.5°  C.).  Parkes  speaks  of  a 
march  of  400  miles  across  the  Egyptian  desert  by  an  English 
army  in  1800.  The  fatigue  of  the  march  was  probably  never 
exceeded  by  any  army.  No  spirits  were  served,  and  the  men 
kept  in  strikingly  good  health.  One  day  some  of  the  soldiers 
obtained  some  date  brandy  and  became  intoxicated,  and  during 
the  following  three  months  a  considerable  number  of  these  men 
were  in  the  hospital. 

Summary  as  to  Food  Value. — We  might  state  our  conclusions 
from  the  scientific  evidence  as  follows : 

Alcohol  cannot  build  up  tissue,  but  it  can  spare  or  replace 
fats  and  carbohydrates  in  the  food,  and  can  prevent  excessive 
protein  destruction  (tissue  waste)  for  a  time.  It  may,  therefore, 
serve  as  a  useful  food  in  some  conditions  of  great  exhaustion  or 
waste,  where  the  tissues  would  otherwise  be  broken  down  to 
furnish  the  energy  to  maintain  life.  But  in  any  case  alcohol 
cannot  be  a  profitable  food  for  any  great  length  of  time,  because 
of  its  central  nervous  effects,  and  because  it  causes  too  marked 
wear  and  tear  on  the  body  structures.  It  is  probable  that  in 
most  conditions  any  sugar  will  be  a  better  food. 

The  use  of  alcohol  as  a  source  of  energy  to  the  body  may  be 
aptly  compared  with  the  employment  of  sea-water  in  a  boiler 
to  produce  steam.  It  will  produce  the  steam  and  run  the  engine 
in  an  emergency,  but  if  its  use  is  continued,  will  eventually  cause 
the  engine's  destruction. 

Alcohol,  therefore,  under  special  circumstances,  may  have  a 
food  value;  but  it  should  not  be  classed  among  the  foods,  because 
its  property  of  yielding  energy  is  not  its  dominant  property,  and 
is  overshadowed  by  important  pharmacologic  actions,  viz.: 

1.  Its  irritant  local  action. 

2.  Its  destructive  action  upon  the  body  tissues. 

3.  Its  narcotic  action. 

4.  Its  proneness  to  result  in  the  formation  of  a  vicious  habit. 
All  these  dominant  properties  place  alcohol  among  the  power- 
ful drugs  and  poisons,  rather  than  among  foods. 


ALCOHOL  337 

As  a  matter  of  fact,  nowadays,  alcohol  to  sustain  one  during 
work  is  very  little  employed.  Persons  who  are  to  undergo  severe 
mental  or  physical  exertion  prefer  to  refrain  from  alcohol  before 
or  during  the  effort,  for  they  find  that  without  the  liquor  they 
can  do  their  work  better,  and  keep  at  it  with  a  clear  mind  for  a 
longer  time.  If  a  strain  is  prolonged,  however,  and  keenness  of 
intellect  is  not  the  first  consideration,  as  in  the  case  of  a  mother 
worn  out  with  anxiety  about  a  sick  child,  a  little  alcohol  may  have 
a  valuable  sustaining  power,  for  it  supplies  readily  absorbable 
food  that  requires  no  gastric  secretion  for  its  digestion;  and,  in 
addition,  through  its  narcotic  effect,  tends  to  lessen  excitability 
and  the  wear  and  tear  upon  the  nervous  system. 

After ,  but  not  during,  a  severe  exertion  or  strain  an  alcoholic 
drink  may  be  of  benefit  for  three  reasons:  (i)  Its  food  value; 
(2)  its  immediate  reflex  exhilarating  effect,  and  (3)  its  subse- 
quent narcotic  or  sedative  effect,  which  promotes  the  feeling  of 
relaxation  and  comfort  and  rest. 

Circulation. — Before  Absorption. — On  the  ingestion  of  strong 
alcoholic  liquors  there  is  an  immediate  rise  in  arterial  pressure, 
the  rate  of  the  beat  being  accelerated.  But  though  the  action 
lasts  only  a  few  moments,  it  is  an  invaluable  one  in  mild  functional 
forms  of  collapse  (feelings  of  faintness,  fainting,  etc.).  From 
experiments  with  unanesthetized  animals,  Brooks  reports  that 
while  alcohol  placed  in  the  mouth  gave  a  striking  reflex  rise  of 
arterial  pressure,  which  returned  to  normal  in  five  or  ten  minutes 
and  was  followed  by  a  slow  fall  in  pressure,  alcohol  placed  in  the 
stomach  through  a  gastric  fistula  gave  no  rise  in  pressure,  even 
in  strengths  up  to  50  and  60  per  cent.  It  is  probable,  therefore, 
that  the  reflex  comes  from  the  mouth.  Well  diluted  alcoholic 
liquors  have  no  reflex  effect. 

After  Absorption. — The  effect  of  alcohol  upon  the  circulation 
after  absorption  has  been  the  subject  of  much  controversy.  Until 
a  few  years  ago  alcohol  was  in  almost  universal  use  as  a  powerful 
heart  stimulant;  while  in  recent  years  the  pendulum  has  swung 
in  the  other  direction,  and  comparatively  little  alcohol  is  pre- 
scribed. It  might  be  in  order,  therefore,  to  review  the  pharma- 
cologic  data  bearing  on  this  point,  remembering  that  studies  in 
animals  anesthetized  by  ether  or  chloroform  tend  to  be  mis- 
leading, because  of  the  similarity  of  the  alcohol  action  to  that  of 
these  anesthetics. 

At  the  Massachusetts  General  Hospital,  Richard  Cabot  made 
1105  observations  in  58  cases  of  typhoid  fever,  pneumonia,  heart 
disease,  cirrhosis  of  the  liver,  pulmonary  and  peritoneal  tuber- 
culosis, and  other  conditions,  to  determine  the  clinical  effect  on 
arterial  pressure.  For  the  first  twenty-four  hours  he  gave  ^ 


338  PHARMACOLOGY   AND   THERAPEUTICS 

ounce  (15  c.c.)  of  whisky,  well  diluted,  every  four  hours,  and 
during  the  second  twenty-four  hours  i  ounce  (30  c.c.)  every 
four  hours.  Observations  were  taken  at  first  at  |-hour  intervals, 
then  every  two  hours,  and  finally  every  four  hours.  In  no  case 
did  either  the  maximum  or  minimum  arterial  pressure  show  any 
change  that  could  be  attributed  to  the  alcohol.  These  are  valu- 
able data,  but  their  importance  must  not  be  exaggerated,  for,  as 
we  have  learned  under  Digitalis,  arterial  pressure,  owing  to  man's 
sensitive  mechanisms  for  regulating  it,  cannot  be  taken  as  a 
measure  of  the  improvement  of  the  circulation  brought  about  by 
a  drug. 

The  laboratory  data  may  be  summed  up  as  follows: 

On  the  Heart. — In  perfusing  the  coronaries  of  a  dog's  isolated 
heart,  Langendorff  and  Loeb,  independently,  found  that  an 
addition  to  the  perfusion  fluid  of  y-g-g-  to  y3^-  of  i  per  cent,  of 
alcohol  (Langendorff  used  o.oi  to  o.i  per  cent.;  Loeb  used  0.13 
to  0.3  per  cent.)  resulted  in  increased  strength  of  systole  and 
increased  output  of  the  heart.  This  was  not  marked,  as  it  would 
be  from  strophanthin  or  epinephrine,  but  was  enough  to  measure. 
If,  however,  more  than  i  per  cent,  of  alcohol  was  added  to  the 
perfusion  fluid,  there  was  muscular  depression  with  dilatation 
of  the  heart  and  stoppage  in  diastole.  Wood  and  Hoyt  (1905), 
working  with  a  reptile  heart,  and  with  a  nutritive  perfusion 
fluid  to  eliminate  any  nutritive  effect  of  alcohol,  obtained  prac- 
tically the  same  results.  With  strengths  of  0.25  and  0.5  per  cent., 
the  output  from  the  heart  was  persistently  increased.  With 
strengths  of  0.5  to  i  per  cent,  there  was  a  primary  increase, 
followed  in  a  few  minutes  by  a  distinct  decrease  in  the  output. 
With  strengths  of  over  i  per  cent,  and  sometimes  with  strengths 
of  less  than  this  the  muscular  activity  decreased  at  once.  On 
changing  from  an  alcoholic  to  a  non-alcoholic  perfusion  fluid, 
the  effect  ceased  quite  promptly,  the  muscle  readily  giving  up  its 
alcohol.  There  were  no  destructive  changes  in  the  heart  muscle 
or  permanent  impairment  of  its  tone. 

On  the  other  hand,  C.  C.  Lieb  (1917)  perfused  the  hearts  of 
rabbits  and  cats  with  Ringer's  solution  free  from  dextrose.  The 
addition  of  alcohol  to  make  concentrations  of  less  than  i  in  50,000 
did  not  affect  the  heart  at  all.  Alcohol  to  make  concentrations 
above  i  in  50,000  resulted,  in  every  case  but  one,  in  a  decrease 
in  the  excursion  and  in  the  total  amount  of  work,  and  usually  in 
a  decreased  rate.  There  was  no  evidence  that  the  normal  heart 
or  the  heart  exhausted  after  prolonged  perfusion  was  capable  of 
utilizing  alcohol. 

In  fatigue  and  debility  experiments  Locke  and  others  have 
shown  that  0.5  per  cent,  of  dextrose  in  the  blood  will  resuscitate 


ALCOHOL  339 

a  partly  exhausted  heart;  and,  as  we  have  seen,  many  experiments 
show  that  alcohol  can  to  some  extent  replace  dextrose  as  a  nutri- 
ent. Therefore  it  may  be  assumed  that  when  other  food  material 
is  not  available,  alcohol  can  serve  as  a  nutritive  to  cardiac  muscle 
as  well  as  to  skeletal  muscle. 

Alcohol,  then,  in  moderate  quantities,  acts  slightly  as  a 
direct  stimulant  to  the  heart  muscle,  and  also  probably  in  de- 
bilitated persons  as  energy-supplying  food  for  the  heart.  In 
nervous,  restless,  excited  persons  it  may  result  in  a  secondary 
quieting  of  the  heart  through  its  narcotic  effect. 

The  rate  of  the  heart  is  quickened,  at  first  because  of  the  reflex 
effect  from  the  mouth,  later  because  of  direct  depression  of  the 
vagus  center  (Dodge  and  Benedict). 

Arteries. — From  ordinary  amounts  there  is  regularly  no 
change  in  arterial  pressure,  but  when  intoxicating  doses  are 
given,  there  is  a  slow  and  very  gradual  moderate  fall.  The 
arterioles  are  dilated,  as  shown  by  the  increase  in  volume  of  an 
organ  placed  in  an  oncometer.  This  is  due  to  depression  of  the 
vasoconstrictor  center,  for  in  an  animal  with  spinal  cord  severed 
to  cut  off  central  control  of  the  splanchnic  arteries  the  pressure 
tends  to  rise.  In  perfusion  of  an  isolated  viscus  there  is  no 
effect  on  the  arteries  unless  the  alcohol  percentage  is  above  that 
compatible  with  life. 

Brooks,  experimenting  with  unanesthetized  animals,  found 
that,  about  fifteen  minutes  after  alcohol  was  placed  in  the 
stomach  through  a  gastric  fistula,  there  resulted  a  very  gradual 
fall  in  pressure  that  lasted  about  an  hour.  When  the  alcohol 
was  given  intravenously  in  small  amounts,  there  was  either  no 
change  in  pressure,  or  a  slight  fall,  followed  by  rapid  recovery; 
from  large  amounts  there  was  a  continuous  and  gradual  fall, 
with  decreased  amplitude  of  the  pulse  and  increased  rate. 

Though,  ordinarily,  there  is  no  rise  in  arterial  pressure,  the 
rate  of  flow,  as  measured  by  the  stromuhr,  is  increased  (Wood 
and  Hoyt).  This  means  a  greater  supply  of  blood  to  the  organs, 
an  effect  not  appreciated  from  blood-pressure  experiments. 

The  cutaneous  arterioles  are  regularly  dilated,  even  from 
therapeutic  doses,  so  that  the  skin  is  flushed,  and  there  is  a 
feeling  of  warmth  and  comfort  and  a  tendency  to  sweating. 
In  susceptible  persons  even  a  teaspoonful  of  a  strongly  alcoholic 
tincture  is  enough  to  flush  the  face  or  even  to  give  a  feeling  of 
light-headedness. 

Summary  of  Effects  upon  the  Circulation: 

i.  Before  Absorption. — Reflex  stimulation  and  rise  in  arterial 
pressure  from  local  irritation  of  the  mouth  or  throat.  This  is 
the  main  action  upon  the  circulation. 


340 


PHARMACOLOGY   AND   THERAPEUTICS 


2.  After  Absorption. — (a)  From  moderate  amounts,  slight 
direct  stimulation  (Langendorff,  Loeb,  Wood  and  Hoyt),  slight 
depression  (Lieb)  of  the  heart  muscle,  and  dilatation  of  the  skin 
vessels;  from  large  amounts,  direct  depression  of  the  heart  muscle. 
(b)  Depression  of  vasoconstrictor  and  vagus  centers,  (c)  Ac- 
celeration of  blood-flow  without  rise  in  blood-pressure,  (d) 
Dilatation  of  the  skin  vessels,  (e)  In  debility  it  may  serve  as  a 
source  of  energy  for  the  heart. 

Respiration. — Willmann  gave  a  rabbit  a  little  oil  of  mustard 
in  10  c.c.  of  saline  by  mouth.  There  was  no  effect  on  respiration, 
though  the  stomach  mucosa  was  very  red  and  irritated.  He 
gave  a  rabbit  alcohol,  and  though  the  stomach  did  not  show 
any  irritation  and  did  not  differ  from  that  of  a  control,  there  was 
great  increase  in  the  depth  and  frequency  of  respiration.  He 
believed,  therefore,  that  the  stimulus  was  not  from  irritation  of 
the  stomach. 

Experiments  were  also  made  on  human  beings  by  Binz  and 
his  pupils.  In  one  case,  for  example,  i\  ounces  (75  c.c.)  of  old 
sherry  was  given  at  8.25  A.  M.  The  respiration  rose  from  3  to 
4.25  liters  of  air  per  minute,  reached  5  liters  at  10.30,  then  fell 
again,  but  was  4  liters  at  11.30.  The  student  was  somnolent 
during  this  time,  as  he  was  unaccustomed  to  wine. 

To  test  the  effect  on  respiration  in  fatigue,  a  boy  of  fifteen 
years,  weighing  45  kilos,  was  given  20  c.c.  alcohol  plus  12  gm. 
sugar,  a  little  lemon-juice,  and  80  c.c.  water.  How  much  effect 
the  sugar  would  have  was  not  determined.  The  effects  were  as 
follows : 


(a)  When  not  fatigued  —in  10  minutes  after  alcohol- 

40 
60 

(b)  When  slightly  tired — in  10 

3° 
40 

(c)  When  very  tired      —in  10 

3° 
40 


airresp.=  +    6.39  per  cent. 

=  +  2.74 
=  —  7-77 

=  +  I2.0O 
=  +  11.20 
=  +  4-25 

=  +  26.80 
=  +  33.10 
=  +  52.34 


Weissenfeld  tested  74  cases,  and  Wendelstadt,  55.  These 
men,  and  Zuntz  and  Bardez,  von  Jaksch,  and  Geppert  obtained 
uniformly  similar  results.  Allen  and  Dubois  found  that  "the 
ingestion  of  alcohol  in  diabetes  was  sometimes  followed  by  respira- 
tory quotients  higher  than  would  be  theoretically  expected." 

Therefore  alcohol  during  fasting  or  fatigue  causes  a  consider- 
able increase  in  respiration,  the  same  increase  occurring  during 
sleep.  "The  increase  is  apparently  central,  and  is  greatest 
from  wines  because  of  their  ethers"  (Binz). 


ALCOHOL  341 

Loewy's  experiments  seem  to  show  that  there  is  no  increase 
in  the  sensitiveness  of  the  center  to  carbon  dioxide,  and  the  exact 
site  of  action  of  alcohol  in  increasing  respiration  is  not  known. 
In  late  stages  of  poisoning  the  respiratory  center  becomes  greatly 
depressed. 

Temperature. — Through  the  dilatation  of  the  skin  vessels 
and  the  sweating,  alcohol  increases  the  dissipation  of  heat,  and 
so  tends  to  lower  the  temperature.  As  the  skin  is  the  seat  of 
the  important  temperature  nerve-endings,  the  great  amount  of 
blood  in  the  skin  vessels  gives  a  feeling  of  warmth.  It  also  makes 
one  more  susceptible  to  changes  in  the  surrounding  temperature, 
so  that  though  on  a  cold  day  a  drink  of  whisky  may  make  one 
feel  warm,  it  is  a  spurious  warmth;  for  the  dilatation  of  the 
skin  vessels  which  makes  the  feeling  of  warmness  results  in  more 
blood  being  brought  to  the  surface  to  be  cooled,  so  that  the  body 
temperature  falls.  In  other  words,  there  is  excessive  heat  Dis- 
sipation. In  arctic  explorations  the  men  are  never  allowed 
liquor  at  all,  because  it  makes  them  more  susceptible  to  cold. 
Whisky  is  often  effectively  employed  to  prevent  a  cold  after 
exposure,  on  the  theory  that  dilatation  of  the  cutaneous  arte- 
rioles  will  counteract  the  results  of  chilling  of  the  surface.  In 
very  hot,  humid  weather  alcohol  predisposes  to  heat-stroke, 
but  this  is  probably  due  to  its  effect  on  the  central  nervous 
system. 

Heat  production  shows  an  increase  during  the  stage  of  intoxi- 
cation owing  to  the  increased  activity,  and  a  decrease  during  the 
stage  of  stupor,  owing  to  depression  of  activity.  Alcohol  in 
medicinal  amounts  is  regularly  a  mild  antipyretic. 

It  might  be  thought  that  the  oxidation  of  alcohol  would 
result  in  excessive  heat  production,  but,  as  we  have  learned, 
alcohol,  in  being  oxidized,  does  not  increase  the  normal  oxida- 
tion, but  merely  replaces  a  part  of  the  normal  oxidizable  material, 
i.  e.,  food. 

Elimination. — Von  Noorden  states  that  1.5  to  6  per  cent,  is 
eliminated  in  the  breath,  i  to  2  per  cent,  in  the  urine,  and  traces 
in  the  sweat.  As  we  have  seen  above,  from  6  one-ounce  doses 
of  whisky  a  day  as  little  as  1.9  per  cent,  may  escape  combustion 
(Atwater  and  Benedict),  and  if  quantities  above  6  ounces  are 
taken,  aldehyde  and  other  incompletely  oxidized  bodies  may  ap- 
pear in  the  breath  and  urine  (Goddard).  Alcohol  never  appears 
in  the  feces;  nor  from  any  beverage  amount  does  it  appear  in  the 
milk  of  nursing  mothers  or  affect  its  quality  (Rosemann,  Kline- 
mann).  When  taken  by  7:  pregnant  woman,  Xicloux  found  it 
in  the  same  percentage  in  the  fetal  blood  as  in  the  mother's  blood. 
The  odorous  principles  of  wines  and  distilled  liquors  are  excreted 


342  PHARMACOLOGY   AND   THERAPEUTICS 

by  the  lungs,  and  tend  to  pervade  the  breath  in  somewhat 
modified  form. 

Uterus. — In  experiments  with  pregnant  rabbits  alcohol  in 
intoxicating  amounts  frequently  caused  abortion. 

Kidneys. — After  excessive  drinking  there  is  regularly  an 
increase  in  the  excretion  of  urine.  This  may  be  the  result  of 
irritation  of  the  kidney  parenchyma,  or  of  the  ingestion  of  a 
large  amount  of  fluid;  or,  as  in  the  case  of  ether,  it  may  result 
from  a  secondary  dilatation  of  the  renal  arterioles.  Long- 
continued  alcohol  drinking  may  be  a  factor  in  the  production 
of  chronic  nephritis.  Warthin  says  he  has  never,  postmortem, 
seen  a  normal  kidney  in  an  alcoholic.  The  alcoholic  kidney  is  of 
the  sclerotic  type,  but  may  look  fairly  normal  to  the  naked  eye. 
It  is  often  not  evident  clinically. 

Bladder. — In  drunkenness  there  may  be  increased  secretion 
of  urine,  yet  at  the  same  time,  owing  to  depression  of  the  reflexes, 
there  may  be  inability  to  empty  the  bladder.  If  the  bladder 
becomes  greatly  distended,  the  urine  must  be  drawn  off  by 
catheter. 

The  Urine. — Reid  Hunt  has  shown  that  the  ethereal  sul- 
phates of  the  urine  are  trebled  in  amount  within  a  week  of  the 
commencement  of  regular  doses  of  alcohol,  and  that  the  neutral 
sulphur  is  decreased.  In  drunkenness  alcohol  appears  in  the 
urine,  even  up  to  0.57  per  cent.,  and  if  it  is  below  i  in  1000  the 
person  is  not  intoxicated  (Widmark). 

Excretion  of  Uric  Acid. — In  connection  with  the  effect  of 
alcohol  upon  physiologic  oxidations  by  the  liver,  and  because  of 
the  relation  of  alcoholic  drinks  to  gout,  the  uric-acid  factor  be- 
comes one  of  importance.  While  after  alcohol  some  workers 
(Noms  and  Smith,  Beebe,  Rosenfeld,  Mendel  and  Hilditch)  have 
found  an  increase  in  the  uric  acid  excreted  in  health,  others 
(von  Noorden,  Leber,  Rosemann,  Chittenden,  Hammett)  have 
found  no  increase.  After  one  or  two  bottles  of  wine  there  is  no 
change  in  the  uric-acid  excretion  (Rosemann),  but  after  beer,  a 
purin-containing  liquid,  the  uric  acid  rises.  (The  malt  liquors 
contain  about  0.145  gm.  purins  per  liter,  while  wines  are  free 
from  purin  bases — Strauss.)  Mandel  found  that  while  refraining 
from  food  a  young  man  excreted  the  same  amount  of  uric  acid 
when  he  took  900  c.c.  of  whisky  as  when  he  took  nothing.  In 
healthy  young  men  (students),  unaccustomed  to  alcohol,  and 
on  a  general  mixed  diet,  Beebe  got  a  distinct  increase  in  the  uric 
acid  after  alcohol,  but  no  increase  when  the  men  were  placed  on 
a  purin-free  diet.  These  experiments  indicate  that  the  amount 
of  exogenous  uric  acid,  that  derived  from  purins  in  the  food,  may 
or  may  not  be  increased  by  alcohol,  but  that  the  amount  of  endogenous 


ALCOHOL  343 

uric  acid,  derived  from  cell-metabolism,  is  uninfluenced.  Lusk  is 
of  the  opinion  that  the  increase  in  exogenous  uric  acid  may  be  due 
to  an  interference  by  alcohol  with  the  formation  of  the  normal 
oxidizable  cleavage-products,  or,  in  other  words,  is  due  to  the 
effect  of  alcohol  upon  the  food,  rather  than  to  its  effect  upon 
the  liver.  Beebe  thinks  that  alcohol  interferes  with  the  urico- 
lytic  power  of  the  liver. 

In  gout  the  results  of  experiments  have  not  been  uniform. 
Most  of  the  experiments  in  subjects  of  chronic  gout  have  been 
performed  during  the  quiescent  stage  of  the  gout,  and  show  a 
distinct  tendency  of  alcohol  to  lessen  the  excretion  of  uric  acid. 
But  whether  this  lessened  excretion  of  uric  acid  means  increased 
storage  in  the  system,  with  the  ultimate  production  of  a  new 
attack,  or  lessened  formation  of  uric  acid,  has  not  been  fully 
determined.  Yet  clinical  experience  favors  the  view  that  alcohol 
may  precipitate  an  attack  of  gout;  and  particularly  is  this  true 
of  the  malt  liquors,  which  contain  up  to  0.145  gm-  °f  purin  bodies 
per  liter. 

Acidosis  and  Excretion  of  Sugar. — In  diabetes,  the  distilled 
liquors,  and  sometimes  the  dry  wines,  are  allowed  in  moderation; 
the  malt  liquors  and  sweet  wines  are  forbidden  because  of  their 
carbohydrate  ingredients  and  acids.  In  severe  diabetes  both 
the  alcohol  and  the  acids  of  wine  are  harmful.  As  alcohol  is 
oxidized  in  place  of  carbohydrate,  and  as  deficient  oxidation  of 
alcohol  shows  in  the  development  of  acetone  bodies,  it  would 
seem  that  in  severe  diabetes  with  deficient  oxidation,  as  in  acidosis, 
alcohol  is  contraindicated.  Higgins,  Peabody,  and  Fitz  produced 
acidosis  by  a  carbohydrate  free  diet,  and  found  that  not  only  did 
alcohol  fail  to  stop  the  progress  of  the  acidosis  or  to  show  any 
antiketonigenic  action,  but  it  increased  the  oxygen  consumption 
and  the  disagreeable  subjective  symptoms.  After  large  amounts 
of  alcohol,  as  taken  in  a  debauch,  and  in  chronic  alcoholism, 
glycosuria  may  appear  even  in  a  non-diabetic;  and  in  a  diabetic 
there  may  be  not  only  increased  sugar  excretion,  but  the  forma- 
tion of  acetone,  diacetic  acid,  and  beta-oxybutyric  acid,  with 
the  development  of  pronounced  acidosis  and  perhaps  fatal 
diabetic  coma.  (The  writer  had  a  case  in  which  fatal  diabetic 
coma  followed  the  ingestion  of  a  quart  of  claret.) 

Tolerance. — Tolerance  for  alcohol  is  readily  set  up,  owing 
partly  to  an  increased  power  to  oxidize  the  drug,  and  partly  to 
an  increased  resistance  of  the  cells.  Schweisheimer  found  that 
in  unaccustomed  men  intoxication  usually  came  on  when  the 
percentage  of  alcohol  in  tit?  blood  reached  0.05  per  cent.,  but 
sometimes  at  0.02  per  cent.  In  habitues  the  blood  at  the  intoxica- 
tion stage  showed  0.12  to  0.23  per  cent.  After  one  liter  of  wine 


344  PHARMACOLOGY   AND   THERAPEUTICS 

containing  10.35  Per  cent,  of  alcohol,  the  percentage  in  the  blood 
of  a  habitual  drinker  quickly  rose  to  its  maximum,  remained  at 
that  point  about  two  hours,  then  rapidly  fell  to  zero.  The  blood  of 
an  unaccustomed  person  slowly  acquired  its  maximum  percentage 
in  one  and  one-half  to  two  hours,  held  the  same  percentage  for 
five  or  six  hours,  and  did  not  reach  zero  till  about  the  twelfth 
hour.  This  long  period  of  maximum  concentration  in  the  blood  is 
a  special  danger  in  acute  alcoholism  in  the  unaccustomed. 
Schweisheimer  concludes  that  drinkers  acquire  a  progressive 
ability  to  keep  down  the  quantity  and  persistence  of  alcohol  in 
the  blood.  In  unaccustomed  animals  Grahant  found  that  6 
parts  per  1000  in  the  blood  could  be  recovered  from. 

Toxicology. — In  susceptible  people  even  a  teaspoonful  of  a 
strongly  alcoholic  tincture  is  enough  to  flush  the  face  and  make 
the  head  feel  light. 

ACUTE  ALCOHOLISM  is  drunkenness,  and  we  have  already  con- 
sidered its  cerebral  manifestations.  The  inattention  to  what 
is  going  on,  the  maudlin  intellect,  the  uncertain  speech,  the 
staggering  gait,  need  no  description.  Alcoholics  tend  to  be 
pugnacious,  lacrymose,  sleepy,  morose,  cheerful,  or  overpolite, 
according  to  their  temperaments,  or  owing  to  some  special 
action  of  the  liquor.  There  is  some  anesthesia,  so  that  the  pain 
of  an  injury  is  not  felt;  and  there  is  partial  muscular  relaxation, 
so  that  falls  are  less  likely  than  usual  to  result  in  broken  bones. 
This  stage  of  intoxication  persists  for  a  long  time,  but  eventually 
passes  into  that  of  stupor,  i.  e.,  deep  sleep  from  which  one  can  be 
awakened  with  difficulty.  When  aroused  from  this  alcoholic 
stupor,  the  patient  shows  stupidity  and  lack  of  intelligence, 
incoherent  speech,  relaxed  muscles,  and  incoordination,  so  that 
he  will  fall  limp,  or  at  least  have  difficulty  in  walking.  On  being 
left  alone  he  relapses  at  once  into  the  stuporous  sleep.  This  state 
distinguishes  alcoholism  from  morphine  poisoning,  in  which 
the  patient  on  being  aroused  shows  reasonable  intelligence, 
can  speak  distinctly  and  answer  questions,  and  can  be  kept 
actively  walking. 

The  stupor  of  alcoholics  often  verges  closely  on  coma;  but 
even  at  this  stage  it  is  characteristic  of  alcohol  that  pressure  on 
the  supra-orbital  nerve  results  in  wincing  or  will  actually  arouse 
the  patient.  In  this  respect  alcoholic  stupor  or  coma  differs 
from  that  of  uremia,  diabetes,  opium-poisoning,  or  cerebral 
injury,  in  which  pressure  on  the  supra-orbital  nerve  meets  with 
no  response.  Following  the  onset  of  coma,  the  alcoholic  may 
readily  pass  into  collapse  and  die.  Death  is  not  infrequent  also 
from  a  fracture  of  the  skull  received  in  a  drunken  fall,  or  from 
pneumonia  brought  on  by  exposure.  Very  large  amounts  of 


ALCOHOL  345 

strong  liquor  may  produce  death  from  reflex  shock,  an  ending 
which  has  frequently  occurred  from  drinking  large  quantities 
quickly  as  the  result  of  a  bet. 

Treatment. — It  is  the  usual  plan  to  give  plenty  of  fresh  air 
and  let  the  drunkard  sleep  it  off.  Occasionally,  especially  if  he 
nas  smoked  freely,  the  patient  vomits  and  is  much  improved. 
In  some  cases  it  may  be  necessary  to  empty  the  stomach  by  lavage 
or  apomorphine,  or  to  catheterize  the  bladder.  Caffeine  and 
strychnine  are  antidotal.  If  the  patient  goes  into  collapse,  the 
regular  treatment  for  collapse  is  indicated. 

After-effects. — The  systemic  after-effects  resemble  those  of 
ether  anesthesia;  viz.,  coated  tongue,  bad  taste  in  mouth,  loss 
of  appetite,  nausea,  retching,  vomiting,  constipation,  headache 
(bursting  head),  great  restlessness,  mental  depression  (remorse 
or  disgust  with  one's  self),  and  lack  of  energy.  There  are  regu- 
larly thirst  and  desire  for  more  liquor.  There  may  be  paralysis 
of  an  arm  (Sunday-morning  paralysis),  from  the  drunkard  hav- 
ing lain  upon  the  arm  in  such  a  way  as  to  cause  pressure  upon  the 
brachial  plexus. 

Treatment. — As  a  rule,  the  usual  morning  distress  may  be 
treated  effectively  with  aromatic  spirits  of  ammonia,  or  a  hot, 
bitter,  and  carminative  mixture.  This  is  known  as  a  "pick- 
me-up"  or  "morning  tonic."  There  can  hardly  be  any  objection 
to  giving  teaspoonful  doses  of  an  alcoholic  tincture  even  though 
one  is  treating  alcoholism.  A  good  prescription  might  be: 

T^     Tinct.  capsici 5  j  (4  c.c.) 

Tinct.  lavandulae  comp §ss  (15  c.c.) 

Spiritus  ammoniac  aromatic!          q.  s.  ad  §ij  (60  c.c.) 

M.  et  Sig. — One  teaspoonful  in  water  every  one  or  two  hours. 

This  is  to  be  followed  by  a  light  meal  of  oyster  stew,  poached 
egg  on  toast,  or  toast  and  tea.  If  the  patient  is  very  restless, 
bromides  may  be  given  by  mouth  or  morphine  hypodermatically. 
A  dose  of  calomel  tends  to  lessen  the  "bilious"  feeling;  and  when 
there  is  distressing  retching  and  nausea,  lavage  or  a  hypodermatic 
of  an  emetic  dose  of  apomorphine,  repeated,  if  necessary,  will 
clean  the  stomach. 

Chronic  Alcoholism. — It  is  now  quite  generally  considered 
that  inebriety  is  a  neurosis  and  that  the  alcoholic  is  a  mental 
defective  in  some  way.  White  says  that  the  life  history  of  the 
alcoholic  shows  him  to  be  an  inefficient  individual,  and  continuity 
of  effort,  day  in  and  day  out,  is  foreign  to  his  character.  In  other 
words,  he  is  a  neurotic.  The  reaction  to  this  inefficiency  is  an 
effort  to  find  safety,  the  state  of  mind  that  avoids  the  thought  of 
responsibility,  hence  the  resort  to  alcohol.  As  Walsh  says, 


346  PHARMACOLOGY  AND  THERAPEUTICS 

"alcohol  lifts  the  scare."  In  other  words,  alcoholism  involves 
both  mental  deficiency  and  access  to  the  drug.  It  is  surprising 
how  little  an  alcoholic  misses  his  drink  when  he  is  completely 
away  from  it,  as  on  a  long  sea-voyage  or  in  an  institution. 

Inebriates  may,  for  convenience,  be  divided  into  three  classes, 
viz.,  the  steady  drinkers,  the  periodic  drinkers,  and  the  dip'- 
somaniacs.  The  steady  drinkers  are  always  under  the  influence 
of  liquor,  though  not  of  necessity  intoxicated.  The  periodic 
drinkers  are  those  who  drink  to  excess  at  intervals,  being  started 
off  on  the  drinking  bout  by  some  small  provocation  or  added 
responsibility  which  lights  up  their  "fear  neurosis."  They  have 
little  will  power.  They  soon  lose  their  sense  of  responsibility, 
and  tend  to  drink  larger  and  larger  quantities,  though  at  first 
attending  to  business.  They  may  cease  drinking  if  segregated 
for  a  single  day.  Dipsomaniacs  are  the  victims  of  epileptic 
insanity  (Diefendorf). 

In  dipsomania  the  impulse  to  drink  is  immediate  and  irresist- 
ible. It  comes  over  the  victim  like  a  paroxysm.  It  may  occur 
in  persons  who  hold  positions  of  responsibility;  and  these,  during 
the  attack,  may  perform  ruinous  acts  of  business,  commit  social 
offenses,  etc.  In  the  intervals  the  victims  may  drink  temper- 
ately or  not  at  all,  and  there  is  no  fear  that  the  sight  of  liquor 
will  bring  on  a  paroxysm.  In  the  attack  the  drinking  may  last 
only  a  day  or  two,  or  may  continue  in  gradually  increasing 
quantities,  or  with  partial  remissions,  for  weeks;  it  frequently 
terminates  in  prostration,  failure  of  the  patient's  stomach,  and 
nervous  breakdown.  The  patients  may  be  unable  to  remember 
where  they  have  been  or  what  they  have  done.  A  man  who 
had  not  drunk  for  some  time  was  left  a  fortune  on  condition 
that  he  refrained  from  drink  for  a  year.  This  acted  as  the 
exciting  cause  of  an  attack,  and  within  an  hour  of  the  reading  of 
the  will  he  was  intoxicated  (Crothers). 

After  drinking  for  some  time,  the  chronic  alcoholic  may  have 
various  gastro-intestinal  disturbances,  disgust  for  food,  nausea, 
retching,  vomiting,  constipation;  and  there  may  be  an  alcoholic 
gastritis,  with  irritability  of  the  stomach,  a  secretion  of  large 
quantities  of  thick  mucus,  and  a  gastric  juice  of  variable  quality, 
sometimes  highly  acid  and  sometimes  deficient  in  acid.  There 
may  be  a  swollen,  tender  liver.  The  nervous  system  is  severely 
upset,  and  there  may  be  mental  depression,  anxiety,  lack  of 
energy,  loss  of  will  power,  and  great  general  nervousness  and 
restlessness.  He  doesn't  care  to  go  to  work,  smokes  to  excess, 
and  has  a  great  thirst  for  liquors.  In  some  cases  there  is  a  per- 
ipheral neuritis,  usually  of  hands  or  feet,  but  sometimes  in  other 
parts  of  the  body,  with  tingling  and  numbness  or  acute  tenderness. 


ALCOHOL  347 

The  patient  may  display  Korsakoff's  psychosis,  which  is  a 
condition  of  disorientation  with  the  memory  strikingly  at  fault. 
The  patient  may  utterly  fail  to  remember  what  he  was  doing  an 
hour  or  a  few  minutes  before,  how  long  ago  he  came  to  the  hos- 
pital, what  is  his  business,  or  whether  he  is  married  or  not.  He 
thinks  the  physician  is  an  old  friend,  though  he  really  has  not 
seen  him  before;  and,  when  questioned,  will  answer  with  a  feeling 
of  absolute  certainty  what  is  obviously  untrue.  This  psychosis 
is  usually  accompanied  by  peripheral  neuritis. 

What  brings  the  patient  to  the  physician  is  mostly  either 
great  nervousness,  gastric  disturbance,  or  peripheral  neuritis. 
Some  men  seem  to  stand  a  daily  consumption  of  large  quantities 
of  liquor  for  a  very  long  time  without  having  occasion  to  visit  a 
physician ;  others  succumb  readily  to  one  or  other  harmful  effect 
of  the  poison.  The  typical  chronic  alcoholic  gradually  loses  his 
mental  and  physical  vigor,  grows  careless  about  his  person  and 
his  habits,  and  becomes  a  relatively  useless  member  of  society. 
The  venules  of  nose  and  cheek  may  become  visible  from  chronic 
dilatation,  the  eyes  are  watery,  injected,  and  with  a  far-away 
look,  there  is  a  tremor  of  hands,  lips,  and  tongue,  the  sexual 
powers  are  frequently  abolished  (azoospermia),  and  the  organs 
of  the  body  show  striking  pathologic  changes. 

Treatment  of  Chronic  Alcoholism.  —According  to  the  circum- 
stances, the  indications  for  treatment  in  severe  outbreaks  are: 
(i)  To  check  the  craving  for  drink.  (2)  To  allay  nervousness 
and  overcome  insomnia.  (3)  To  supply  nourishment  and  get 
the  stomach  tolerant  to  food.  (4)  To  promote  elimination. 

1.  To  check  the  craving  for  drink.    This  requires — (a)  Gradual 
withdrawal  of  the  alcoholic  drinks  and  (b)   their  replacement 
by    hot,    bitter    carminatives.     (See    Acute    Alcoholism.)     At- 
tempts to  withdraw  the  liquor  suddenly  result  in  a  rebellious 
patient,  and  sometimes  in  serious  mental  and  nervous  mani- 
festations.    For  the  gradual  withdrawal  of  liquor  there  are  two 
plans  in  common  use,  viz. : 

(a)  Allowing  one  ounce  of  whisky  for  each  dose,  the  interval 
between  the  doses  is  lengthened  each  time,  the  second  dose  being 
given  half  an  hour  after  the  first,  the  third  one  hour  later,  the 
fourth  two  hours  later,  etc. 

(b)  Using  a  bottleful  of  whisky,  a  drink  is  given  every  half- 
hour  or  hour,  but  after  each  dose  the  bottle  is  refilled  with  water, 
so  that  the  liquor  becomes  more  and  more  diluted.     After  a  time 
it  is  practically  all  water. 

2.  To  allay  nervousness  ^nd  overcome  insomnia  the  favorite 
remedies  are  bromides  in  large  doses,  morphine  sulphate,  |  grain 
(0.015  gm.)  by  hypodermatic,  hyoscine  hydrobromide  or  atropine 


348  PHARMACOLOGY   AND   THERAPEUTICS 

sulphate,  T|7  grain  (0.0006  gm.)  by  hypodermatic  or  mouthr 
paraldehyd,  2-4  drams  (8-15  c.c.),  chloral  hydrate,  30  grains 
(2  gm.).  The  "narcotic"  method  of  keeping  the  patient  con- 
stantly asleep  for  from  twenty-four  to  thirty-six  hours  has  its 
strong  advocates,  and  even  the  rest  obtained  from  a  hypodermatic 
of  morphine  sulphate,  \  grain,  and  hyoscine  hydrobromide,  y^ 
grain  (0.0006  gm),  may  be  of  great  benefit.  The  cold  bath  and 
the  wet  pack  may  be  needed  in  some  cases. 

3.  To  supply  food,  small  quantities  of  hot  milk,  koumiss, 
oyster-stew,  junket,  calves'-foot  jelly,  etc.,  may  be  administered 
at  frequent  intervals.     As  soon  as  the  stomach  becomes  tolerant, 
milk-toast,  poached  egg  on  toast,  oysters,  etc.,  may  be  allowed. 
Carbohydrates  are  especially  recommended  to  replace  the  alcohol. 
Spitzig  feeds  intensively  with  sugar. 

4.  To  promote  elimination,  valuable  measures  are  plenty  of 
fresh  air,  because  of  excretion  of  the  alcohol  by  the  lungs,  sweat- 
ing by  hot  baths,  or  a  Turkish  bath  if  patient  is  able  to  stand  it, 
and  vigorous  catharsis  with  compound  cathartic  pills,  or  calomel 
followed  by  citrate  of  magnesia. 

Delirium  tremens  ("the  horrors")  is  a  special  manifestation 
of  chronic  alcoholism.  It  rarely  occurs  except  after  continued 
heavy  drinking,  and  in  such  cases  may  be  brought  on  by  the 
sudden  withdrawal  of  the  alcohol  or  by  a  temporary  great  excess, 
by  pneumonia,  or  by  traumatism,  e.  g.,  fracture  of  a  limb.  It 
is  characterized  by  horrible  hallucinations  of  sight  and  hearing. 
The  hallucinations  take  the  form  of  snakes,  rats,  things  crawling 
over  the  body,  or  people  with  harmful  intentions.  The  patient 
sees  them  coming  or  hears  voices.  He  shows  intense  activity, 
talking,  muttering,  crying  out,  attempting  to  get  out  of  bed,  or 
perhaps  to  escape  from  the  attendants.  Insomnia  is  almost 
complete,  and  there  may  be  a  temperature  of  102°  or  103°  F. 
The  patient  may  pass  into  coma  and  die  with  cerebral  edema 
(wet  brain),  or  go  into  collapse  from  pneumonia,  traumatism,  or 
the  excessive  activity  and  struggling. 

The  treatment  is  that  for  chronic  alcoholism,  and  in  addition 
wise  restraint  and  close  watching  of  the  circulation  because  of 
the  tendency  to  collapse.  The  withdrawal  of  liquor  must  be 
managed  more  deliberately.  In  a  study  of  the  treatment  in 
500  cases  Ranson  (1909)  found  ergot  apparently  the  best  remedy. 
The  mortality  in  those  getting  ergot  was  21.6  per  cent,  below  the 
average.  Sceleth  and  Beifeld,  from  an  experience  with  2500  cases 
a  year,  state  that  simple  delirium  tremens  when  treated  lasts  three 
to  eight  days,  while  with  wet  brain  it  lasts  two  to  twelve  weeks,  with 
a  mortality  of  75  per  cent.  They  find  ergot  useful  in  the  asthenic 
cases,  but  harmful  in  wet  brain.  They  recommend  hydrotherapy 


ALCOHOL  349 

and  consider  lumbar  puncture  of  no  value,  though  Dana  and  also 
Steinebach  advocate  it.  Alcohol  has  been  found  in  the  spinal 
fluid.  Hogan  advocates  the  intravenous  use  of  1000  c.c.  of 
a  solution  of  sodium  chloride  0.58  per  cent.,  sodium  bromide 
1.02  per  cent.,  and  sodium  bicarbonate  0.84  per  cent.,  followed 
by  a  solution  of  80  gm.  of  glucose  in  250  c.c.  of  water. 

Late  in  the  course  of  lobar  pneumonia  in  persons  accustomed 
to  much  alcohol  there  is  sometimes  seen  a  peculiar  maniacal 
delirium  verging  on  delirium  tremens.  In  such  cases  the  delirium 
may  not  yield  until  good-sized  doses  of  whisky  or  brandy  are 
administered. 

The  cure  of  alcoholism  depends  on  the  patient's  desire  for 
cure,  on  the  temperament  of  the  patient,  and  on  the  type  of  the 
drinker.  White  says  that  alcohol  is  not  a  habit-drug,  but  that 
the  alcoholic  wants  to  believe  it  a  habit,  so  as  to  excuse  his 
resorting  to  it  to  take  him  away  from  reality,  i.  e.,  the  feeling  of 
inefficiency.  From  a  therapeutic  point  of  view  inebriates  may  be 
classed  as:  those  who  do  not  have  an  irresistible  craving  for 
alcohol,  and  those  who  do  have  the  craving  (Crothers).  The 
former  drink  because  others  do,  or  from  bravado,  or  for  other 
reasons,  and  can  often  be  readily  induced  to  stop  drinking.  The 
latter  are  constant  drinkers,  periodic  excessive  drinkers,  or  dip- 
somaniacs. Their  treatment  is  the  same,  except  that  in  the  case 
of  the  dipsomaniac  restraint  is  a  requisite  at  the  time  of  the 
onset  of  the  attack.  Among  the  favorite  schemes  of  treatment 
are  hyoscine  hydrobromide  or  hyoscyamine  or  atropine  sulphate, 
TijQ-  grain  (0.0006  gm.)  thrice  daily,  which  causes  great  dryness  of 
the  throat  and  a  loss  of  taste  for  the  liquor;  strychnine  sul- 
phate, -JQ-  grain  three  times  a  day,  to  tone  up  the  system;  and 
hot  bitter  carminatives  to  supply  oral  and  gastric  stimulation. 
Doctoring  whisky  with  apomorphine  and  then  allowing  the 
patient  to  drink  whenever  he  wishes  is  another  method  in 
vogue.  The  nausea  and  vomiting  destroy  the  taste  for 
liquor. 

Alexander  Lambert  administers  5  compound  cathartic  pills 
and  5  grains  of  blue  mass  every  twelve  hours  until  green  stools 
appear,  then  2  ounces  of  castor  oil.  During  the  process  he 
gives  to  nervous  or  elderly  persons  2  ounces  of  whisky  four  or 
five  times  in  the  first  twenty-four  hours,  then  only  strychnine  or 
digitalis,  and  a  sleep  mixture  of  chloral  hydrate,  morphine, 
tincture  of  hyoscyamus,  ginger,  and  capsicum.  If  the  patient 
has  an  intolerant  stomach,  he  gives  5  grains  of  sodium  bicar- 
bonate and  5  grains  of  compound  morphine  powder  every  two  or 
three  hours  for  two  or  three  doses.  During  the  whole  treatment 
he  gives  from  2  to  18  drops  every  hour  of  a  mixture  of  two  parts 


350  PHARMACOLOGY   AND   THERAPEUTICS 

of  15  per  cent,  tincture  of  belladonna  and  one  part  each  of  the 
fluidextracts  of  hyoscyamus  and  xanthoxylum. 

The  Pathologic  Effects  on  Organs. — After  drinking  large 
quantities  has  been  the  habit  for  a  long  time,  certain  destructive 
changes  are  prone  to  appear  in  the  organs.  These  are  cirrhosis 
of  the  liver  and  fatty  liver,  chronic  gastritis,  chronic  nephritis, 
myocarditis,  fatty  degeneration  of  the  heart,  arteriosclerosis, 
pulmonary  emphysema,  chronic  leptomeningitis,  peripheral 
neuritis,  various  spinal  and  cerebral  scleroses,  and  atrophy  of 
the  testicles.  In  the  brain-cells  the  chromatin  network  is 
replaced  by  fine  granules  or  lost  in  the  cytoplasm.  The  "wet 
brain,"  i.e.,  edema  of  the  brain  and  meninges,  is  common  in  death 
from  delirium  tremens.  Though  alcohol  is  undoubtedly  an 
important  factor  in  the  production  of  these  lesions,  it  is  believed 
nowadays  that  the  influence  of  alcohol  has  been  exaggerated,  and 
that  there  are  other  important  causative  factors.  At  any  rate 
such  lesions  are  not  infrequently  seen  in  persons  who  have 
not  been  alcoholic.  Simmonds,  of  Hamburg,  found  that  in  100 
cases  of  cirrhosis  of  the  liver  14  were  non-alcoholic.  In  309 
autopsies  on  chronic  alcoholics  at  the  Hafenkrankenhaus,  Fahr, 
of  Hamburg,  found  striking  cirrhosis  in  only  13  cases,  though 
fatty  changes  were  usual.  In  30  per  cent,  there  was  fatty 
infiltration  of  the  heart,  in  20  per  cent,  chronic  gastritis,  in  8 
per  cent,  chronic  nephritis,  in  50  per  cent,  chronic  leptomeningitis. 
Arteriosclerosis  was  rather  less  common  than  among  other  cases 
of  corresponding  age. 

Richard  Cabot  has  looked  up  some  statistics  of  arteriosclerosis 
in  Boston.  Of  283  cases  of  chronic  excessive  alcoholism  under 
fifty  years  of  age,  only  6  per  cent,  showed  evidence  of  arterio- 
sclerosis. Of  45  cases  of  arteriosclerosis,  only  13  per  cent,  gave  a 
history  of  alcoholism.  Of  556  cases  of  arteriosclerosis  found 
postmortem,  only  95  (14.5  per  cent.)  were  under  fifty  years  of 
age,  and  of  this  95,  only  21  per  cent,  appear  to  have  consumed 
alcohol  in  excess. 

The  following  is  Welch's  summary  of  the  pathologic  changes 
in  the  rabbits  used  by  Friedenwald  (1905)  in  studying  experi- 
mental alcoholism.  The  daily  dose  was  5  to  8  c.c.  of  absolute 
alcohol  in  15  to  30  c.c.  of  water,  or  10  to  20  c.c.  of  whisky  diluted 
with  10  to  20  c.c.  of  water. 

i.  Animals  exhibit  marked  individual  differences  in  their 
susceptibility  to  the  injurious  effects  of  the  prolonged  ad- 
ministration of  intoxicating  closes  of  alcohol.  Some  rab- 
bits given  intoxicating  doses  every  day  for  four  years 
presented  no  serious  anatomic  lesion  attributable  to  the 
alcohol,  while  to  similar  doses  others  succumbed  quickly. 


ALCOHOL  351 

2.  The  most  common  pathologic  condition  is  a  fatty  metamor- 

phosis affecting  especially  the  cells  of  liver,  heart  muscle, 
and  kidney,  the  lesion  speedily  disappearing  on  the  stop- 
page of  alcohol.  Necrosis  of  limited  groups  of  cells  in  liver 
and  kidneys  may  occur,  but  is  inconstant.  An  acute  or 
chronic  gastritis  may  appear,  but  is  often  absent.  Hyper- 
emia  and  small  hemorrhages  may  occur,  especially  in 
stomach,  kidneys,  and  brain. 

3.  Alcoholic  intoxication  increases  the  susceptibility  of  ani- 

mals to  many  infections,  and  influences  unfavorably  the 
process  of  immunization.  Pregnant  rabbits  repeatedly 
intoxicated  are  prone  to  abort,  or  many  of  their  young 
die  in  a  few  days  after  birth. 

Reid  Hunt  (1907)  experimented  with  smaller  doses  through 
four  generations  of  guinea-pigs,  and  concluded  that  those  given 
a  few  cubic  centimeters  of  5  to  10  per  cent,  alcohol  with  their 
daily  food  grew  just  as  quickly,  reached  maturity  as  soon,  and 
were  just  as  fertile  as  those  with  no  alcohol.  They  showed  no 
symptoms,  no  loss  of  weight,  no  pathologic  changes. 

The  Liver. — Mcjunkin  (1917)  gave  80  per  cent,  alcohol  daily 
or  on  alternate  days  in  intoxicating  amounts  to  guinea-pigs, 
rabbits,  cats  and  dogs;  the  greatest  number  of  doses  for  any  one 
animal  was  92.  He  also  gave  alcohol  rectally,  subcutaneously, 
intraperitoneally,  by  injection  into  the  common  bile-duct, 
and  by  injection  directly  into  the  liver.  In  no  case  did  he  find 
any  lesion  of  the  liver  similar  to  that  in  human  cirrhosis.  Robert- 
son gave  alcohol  daily  to  dogs  for  over  a  year,  and  the  liver 
showed  no  changes.  Grover,  by  15  c.c.  daily  of  34  per  cent, 
alcohol  in  the  empty  stomach,  obtained  a  beginning  cirrhosis 
after  several  months  in  5  out  of  12  rabbits.  (See  also  Liver, 
p.  326.) 

The  Kidneys. — Hultgen  (1910)  reported  461  cases  of  chronic 
alcoholism  with  clinical  evidences  of  nephritis  in  9.1  per  cent., 
and  albuminuria  in  5.2  per  cent.,  and  called  attention  to  the 
report  of  Dickinson  in  Allbutt's  System  that  in  48  autopsies 
of  those  who  died  of  alcohol  there  was  no  greater  proportion  of 
contracted  kidneys  than  in  48  postmortems  of  persons  of  the 
same  age  who  were  not  alcoholics.  But  A.  S.  Warthin  states 
that  he  has  never  seen  a  normal  kidney,  postmortem,  from  an 
alcoholic,  and  criticizes  Hultgen's  diagnosis  as  clinical  and  not 
histologic. 

Gideon  Wells  describes  the  alcoholic  kidney  as  of  the  "hog- 
back" type,  fat  and  rounded,  and  normal  looking,  but  really 
sclerotic  and  with  a  diminished  number  of  capable  glomeruli. 
In  the  author's  experience  it  may  fail  to  give  urinary  evidences 


352  PHARMACOLOGY   AND   THERAPEUTICS 

unless  the  urine  is  examined  morning  and  evening  and  day  after 
day. 

Fecundity  and  Heredity. — Stockard's  long-continued  experi- 
ments with  guinea-pigs  exposed  to  the  fumes  of  alcoholism  for 
six  days  a  week  almost  to  the  point  of  intoxication  give  informa- 
tion of  great  interest.  In  1916  he  published  records  of  1115 
offspring  produced  by  887  matings.  The  alcoholic  females 
were  slow  to  conceive,  not  prolific,  and  in  many  cases  almost  or 
quite  sterile.  In  180  matings,  of  which  one  or  both  parents 
were  alcoholized,  there  were  40  per  cent,  of  negative  results  or 
early  abortions,  while  in  the  controls  there  were  2 1  per  cent. 

The  mating  records  of  the  first  generation  of  descendants  of 
the  alcoholized  guinea-pigs,  although  themselves  not  treated  with 
alcohol,  show  that  in  140  living  litters  there  were  238  young,  of 
which  102  died  within  a  few  days,  about  13  per  cent,  of  them 
being  deformed,  and  136  survived,  8  per  cent,  of  them  showing 
eye  deformities.  Of  186  control  young  of  the  same  stock  not 
alcoholized  not  one  was  deformed.  The  succeeding  generations 
became  weaker  and  less  prolific.  Structural  defects  were  numerous 
and  were  confined  largely  to  the  central  nervous  system  and  the 
special  sense  organs.  The  female  offspring  from  alcoholic  males 
and  the  male  offspring  from  alcoholic  females  showed  special 
inferiority. 

Gordon  (1916)  studied  the  pedigrees  for  four  generations  in 
three  alcoholic  human  families,  and  found  various  degrees  of 
mental  deficiency,  striking  feeble-mindedness,  epilepsy,  violent 
temper,  somnambulism,  tremors,  and  choreiform  movements. 
In  four  generations  there  were  only  3  normal  descendants  of  the 
alcoholic  males.  Stockard  quotes  Sullivan's  observation  of  a 
sober,  industrious  woman  who  married  three  times.  The  first  and 
third  husbands  were  sober,  and  with  the  first  there  were  three 
normal  children,  and  with  the  third  two  normal  children.  The 
second  husband  was  a  drunkard,  and  of  this  union  there  were 
three  children,  one  of  which  became  a  drunkard,  one  an  epileptic, 
and  one  a  degenerate. 

Resistance  to  Disease. — There  is  evidence  that  medicinal 
quantities  of  alcohol  increase  the  susceptibility  to  bacterial  in- 
vasion or  increase  the  danger  of  toxemias  in  acute  illness;  and 
there  is  no  doubt  that  the  taking  of  alcohol  in  large  quantities 
day  after  day  for  many  years  results  in  impairment  of  the  body 
structures,  lessens  resistance  to  many  infections,  influences  un- 
favorably the  processes  of  immunization,  and  diminishes  the  heal- 
ing power  of  injured  tissues.  There  is  a  well-recognized  high 
mortality  among  alcoholics  in  pneumonia  and  tuberculosis. 
Laitinen  reports  a  greater  susceptibility  to  infection  and  greater 


ALCOHOL  353 

mortality  if  much  alcohol  is  used,  but  not  much  from  the  pro- 
longed use  of  small  quantities  (o.i  c.c.  per  kilo,  i.  e.,  ^  ounce 
(15  c.c.)  of  whisky  for  a  man). 

Rubin  found  that  a  hypodermatic  of  alcohol,  ether,  or  chlo- 
roform would  render  rabbits  more  susceptible  to  streptococcus 
and  pneumococcus  infections;  Stewart,  that  a  small  amount  of 
alcohol  lowers  the  opsonic  index  to  the  bacillus  tuberculosis  and 
streptococcus,  and  Graham  that  animals  given  alcohol  or  ether 
succumb  more  readily  to  experimental  infection  than  controls, 
especially  in  those  diseases  of  which  the  immunity  is  chiefly 
phagocytic.  Lyon  Smith  found  that  in  animals  doses  equivalent 
to  2  ounces  (60  c.c.)  for  a  man  of  140  pounds  (70  kilo.)  increased 
phagocytic  activity,  while  doses  equivalent  to  10  ounces  (300  c.c.) 
destroyed  it;  while  Parkinson  found  that  it  had  no  action  on 
phagocytic  activity  if  present  in  a  strength  below  12.5  per  cent. 
In  anaphylactic  experiments,  Besredka  found  that  animals  to 
which  alcohol  was  given  following  the  sensitizing  dose  were 
more  resistant  to  the  anaphylactic  dose. 

Alcohol  in  mildly  intoxicating  quantities  for  several  days 
after  the  injection  of  the  antigen  retards  the  formation  of  the 
antibodies  (Miiller,  1904;  Wirgin  1905);  but  the  results  of 
others'  experiments  seem  to  indicate  a  favorable  action  in  the 
formation  of  antibodies  from  a  single  mildly  toxic  dose  of  alco- 
hol at  or  near  the  time  the  antigen  is  introduced.  Laitinen  found 
it  difficult  to  immunize  alcoholized  animals  to  diphtheria  toxin. 
Parkinson  found  that  a  small  dose  in  rabbits  might  stimulate 
the  production  of  antibodies  temporarily  and  that  it  lessened 
the  reacting  mechanism  to  vaccines;  that  a  large  dose  will  lower 
the  opsonic  index  for  twenty-four  hours,  and  that  continued 
moderate  doses  cause  a  permanent  lowering  of  the  opsonic 
index. 

Preventives. — Leonard  Hill  reports  that  in  alcohol  poisoning 
fatty  infiltration  of  the  liver  is  prevented  by  feeding  glycogen- 
buiklers,  i.  e.,  carbohydrates.  Dogs  which  on  pure  fat  diet  put 
on  25  per  cent,  of  dry  liver  substance  as  fat,  have  this  per  cent, 
lowered  to  one-half  or  less  by  the  feeding  of  glycogen-builders 
at  the  same  time.  Von  Noorden  noted  that  the  percentage  of 
fat  in  both  heart  and  liver  of  starved  dogs  increases  from  alcohol 
in  a  few  days,  but  that  this  effect  is  prevented  by  sugar.  Similar 
though  less  marked  protection  of  the  liver  has  been  reported  from 
sodium  bicarbonate. 

Therapeutics. — External. — As  antiseptic,  as  in  cleansing  sur- 
geon's hands  or  skin  of  patient.  As  cooling  lotion  in  headache 
or  in  itching  or  for  bruises  (eau  de  cologne,  spirit  of  camphor, 
witch-hazel,  or  tincture  of  arnica).  For  rubbing  the  body  of  an 


354  PHARMACOLOGY  AND  THERAPEUTICS 

invalid,  50  to  95  per  cent,  alcohol  is  very  refreshing,  and  in  fever 
is  cooling.  As  anhidrotic  in  sweating  of  the  hands  and  feet  and 
in  the  night-sweats  of  tuberculosis.  To  harden  the  skin,  as  when 
bed-sores  are  threatened.  In  refractory  trigeminal  neuralgia,  15 
minims  (i  c.c.)  may  be  injected  into  the  nerve. 

As  a  preventive  of  carbolic  acid  burns,  alcohol  is  the  best  remedy. 
Its  affinity  for  the  phenol  being  greater  than  that  of  the  tissues, 
it  prevents  penetration  of  the  carbolic.  When  the  carbolic  is 
swallowed,  alcohol  is  best  given  in  the  form  of  whisky,  but  it 
should  be  at  once  washed  out;  for  though  it  lessens  the  local 
effect,  it  may  increase  the  absorption  of  the  carbolic  and  hence 
the  systemic  poisoning. 

Alimentary  Tract. — For  their  effect  on  appetite  and  digestion 
alcoholic  drinks  may  be  employed  in  convalescence  and  debility, 
and  in  conditions  of  diminished  gastric  secretion;  for  their  car- 
minative action,  in  flatulence  and  colic;  for  their  reflex  stimulat- 
ing effect,  in  faintness  and  fainting.  For  the  carminative  and 
reflex  stimulating  effect  the  fortified  wines  and  distilled  liquors 
are  employed.  Ice-cold  brandy  and  champagne,  especially 
the  latter,  because  of  the  CO2  it  contains,  are  employed  in  sea- 
sickness and  other  forms  of  intractable  nausea  and  vomiting. 
Brandy  is  a  favorite  remedy  in  summer  diarrhea. 

For  systemic  effect  whisky  and  brandy  are  mostly  employed: 

1.  To  prevent  or  check  a  cold  after  exposure. 

2.  To  furnish  food  and  stimulation  in  depressed  conditions, 
and  in  convalescence  from  acute  illness  (milk-punch) . 

3.  As  a  narcotic  or  sedative  in  states  of  nervousness,  restless- 
ness, or  delirium;  in  the  delirum  of  alcoholics  it  may  be  especially 
necessary. 

4.  As  hypnotic  in  mild  chronic  forms  of  insomnia,  as  from 
mental  work  late  at  night  or  continued  nervous  strain  (beer,  ale, 
or  whisky  taken  at  bed-time). 

5.  In  fever,  as  antipyretic,  as  food,  and  as  narcotic  to  allay 
nervousness  and  restlessness  and  promote  quiet  and  sleep,  but 
it  lowers  resistance. 

6.  In  shock. — In  surgical   shock  it  tends  to  diminish  the  al- 
ready lowered  blood-pressure   (Crile);  but  in  mild  degrees  of 
shock,  where  consciousness  is  not  abolished,  as  in  emotional 
shock  or  mild  trauma,  the  condition  may  be  improved  both  by 
the  reflex  stimulation  of  the  surface  irritant  action  and  by  the 
narcotic  effect  upon  the  excited  mind. 

The  use  of  alcohol  in  medicine  has  become  very  much  limited 
in  recent  years,  and  we  no  longer  sec  a  pneumonia  patient  del- 
uged with  one  or  two  pints  of  whisky  a  day,  or  one  with  tuber- 
culosis feeding  on  innumerable  milk-punches.  That  its  real  value 


METHYL   ALCOHOL  355 

in  many  cases  is  due  to  its  narcotic  or  sedative  effect  has  not  been 
fully  appreciated. 

Contraindications. — Gastric  ulcer,  gastric  hypersecretion,  hy- 
perchlorhydria,  intestinal  autointoxication,  cirrhosis  of  the  liver, 
nephritis,  cystitis,  urethritis,  chronic  eczema,  and  gout.  In  dia- 
betes the  sweet  wines  and  malt  liquors  are  distinctly  contraindi- 
cated,  and  it  is  open  to  question  if  even  a  dry  wine  should  be 
allowed. 

Where  it  is  known  that  the  patient  has  been  an  alcohol 
habitue,  it  is  criminal  to  prescribe  an  alcoholic  drink,  and  it  is 
the  duty  of  the  physician  to  consider  well  before  prescribing  any 
medicine  with  a  distinctly  alcoholic  or  vinous  flavor.  In  sickness 
it  is  equally  imperative  to  use  judgment  before  cutting  off  the 
alcohol  from  a  drinker;  it  will  not  do,  for  example,  to  stop  the 
whisky  of  a  chronic  drinker  during  an  attack  of  pneumonia. 

METHYL  ALCOHOL 

Methyl  alcohol,  wood  naphtha,  or  wood  alcohol,  CH3OH,  is 
not  employed  as  a  remedy,  but  is  of  interest  because  of  the  number 
of  cases  of  poisoning  following  its  use.  Its  local  and  central 
actions  are  similar  to  those  of  ethyl  alcohol,  and  it  can  produce  a 
somewhat  similar  intoxication,  though  the  onset  is  slower  and  the 
depression  or  narcotic  condition  more  prolonged.  But  two  strik- 
ing differences  are  that  it  is  not  readily  excreted  and  is  not  fully 
oxidized.  Indeed,  its  products  in  the  body  are  formic  acid  and 
formaldehyd,  and  it  is  thought  that  these  substances,  or  per- 
haps acetone  and  other  bodies  always  present  in  the  commercial 
article,  may  account  for  its  especially  deleterious  effects.  These 
effects  are  of  two  kinds,  viz.,  atrophy  of  the  optic  nerve,  with 
permanent  blindness,  and  depression  of  cardiac  and  voluntary 
muscle,  resulting  in  death.  Birch-Hirschfeld  (1916)  notes  that 
the  symptoms  do  not  develop  for  several  hours  or  days,  and 
begin  by  nausea,  vomiting,  dizziness  and  headache,  progressing 
rapidly  to  delirium  and  convulsions.  The  poisoning  should  be 
suspected  when  toxic  gastro-intestinal  symptoms  occur  with 
sudden  severe  disturbances  in  vision,  with  central  scotoma, 
contraction  of  the  field  of  vision,  and  optic  neuritis.  Krol 
reports  a  pronounced  acidosis.  Thompson  says  it  is  strongly 
hemolytic.  The  treatment  consists  of  plenty  of  fresh  air  and 
copious  alkali-water-therapy  to  promote  elimination. 

Buller  and  Wood  collected  54  cases  with  blindness  in  the  United 
States  and  Canada,  some  of  vvhich  died,  and  since  then  a  great 
many  cases  of  either  blindness  or  death  have  been  reported.  After 
one  celebration  on  doctored  whisky  at  Dorpat,  Russia,  16  men 


356  PHARMACOLOGY   AND   THERAPEUTICS 

and  i  woman  died,  and  3  men  became  blind.  At  Stryker's  Farms, 
near  New  York,  25  died  from  drinking  a  cheap  whisky  made  of 
methyl  alcohol.  In  the  Berlin  municipal  lodging-house,  in  the 
month  of  December,  1911,  there  were  89  deaths  and  5  cases  of 
total  blindness  due  to  wood  alcohol  in  cheap  spirits.  There  are 
many  other  instances  of  recent  date. 

These  deaths  have  usually  followed  debauches  with  adulter- 
ated whisky.  But  many  instances  of  blindness  have  come  from 
the  inhalation  of  fumes  in  its  industrial  use,  and  from  hair-tonics, 
bay-rum,  cologne-water,  essence  of  ginger,  and  other  pharmaceu- 
ticals  in  which  wood  alcohol  has  been  substituted  for  grain 
alcohol.  As  small  an  amount  as  0.2  per  cent,  in  the  inspired  air 
may  lead  to  poisoning  (Loewy).  Because  of  many  cases  in  New 
York  city,  the  Health  Department  has  an  ordinance  forbidding 
the  use  of  methyl  alcohol  in  any  preparation  for  internal  or 
external  human  use. 

HYPNOTICS 

A  hypnotic  is  a  remedy  employed  to  induce  or  to  maintain 
sleep.  Leonard  Hill  summarizes  as  follows  the  facts  which  are 
known  concerning  sleep: 

j.  Respiration. — (a)  The  number  per  minute  remains  unal- 
tered; the  movement  becomes  shallow  and  thoracic  in  type; 
(6)  the  amount  of  inspired  air  per  minute  is  lessened  by  from 
one-half  to  two-thirds;  (c)  the  output  of  CO2  is  diminished  by 
one-half  to  two-thirds. 

2.  Circulation. — (a)  The  blood  congests  in  the  limbs;  (b}  the 
venous  system  is  engorged;  (c)  the  arterial  pressure  falls;  (d)  the 
pulse-rate  diminishes;  and  (e)  the  velocity  of  blood-flow  decreases. 

j.  Temperature. — The  temperature  falls  during  the  night. 
The  production  of  heat  is  estimated  to  diminish  by  from  one- 
half  to  two-thirds. 

4.  Nervous  System. — (a)  The  blood-flow  through  the  brain  is 
diminished;  (b)  the  acidity  of  the  cortex  decreases;  (c)  the  ex- 
citability of  consciousness  to  external  stimuli  steadily  decreases 
during  the  first  one  to  two  hours  of  sound  sleep.  After  that 
period  the  excitability  rapidly  becomes  almost  as  great  as  it  is 
toward  the  end  of  sleep;  and  (d)  consciousness  alone  seems  to  be 
abrogated  during  sleep.  The  nerves  and  the  special  senses  con- 
tinue to  transmit  impulses  and  produce  reflex  movements. 

Verworn's  Theory. — Sleep,  as  pointed  out  by  Verworn,  is 
entirely  different  from  narcosis.  Sleep  comes  because  of — (i) 
The  lessened  irritability,  i.  e.,  fatigue,  of  the  cells  of  the  cerebral 
cortex  which  results  from  work;  and  (2)  the  removal  of  external 
stimuli,  as  noise,  lights,  etc.  Narcosis  comes  from  direct  and 


HYPNOTICS  357 

deliberate  depression  of  the  cells  of  the  cerebral  cortex.  In  sleep 
the  cells  recover  from  fatigue,  regain  their  lost  irritability,  and 
are  restored  to  their  full  capacity  for  work;  in  other  words,  sleep 
implies  restitution.  In  narcosis,  on  the  other  hand,  there  is  no 
restitution,  and  the  cells  lose  their  irritability  and  go  through 
the  stages  of  fatigue  production.  A  narcotic  is  prone  to  be  fol- 
lowed by  sleep  because  it  produces  fatigue  of  the  cells,  and  when 
a  narcotic  substance  is  given  to  produce  sleep  (i.  e.,  a  hypnotic), 
it  does  so  by  depressing  the  cells  and  thus  reducing  the  excita- 
bility of  the  cerebral  cortex  which  is  preventing  sleep.  The 
depression  of  the  cells  thus  produced  may  then  be  followed  by 
restorative  sleep,  but  the  hypnotic  does  not  directly  or  primarily 
induce  natural  sleep. 

If  too  much  of  the  hypnotic  is  given,  the  primary  narcosis  is 
not  followed  by  restorative  sleep,  but  continues  for  a  long  time, 
and  results  in  fatigue  of  the  cerebral  cells  instead  of  restoration. 
This  effect  is  sometimes  seen  during  the  following  day,  especially 
in  old  people,  and  it  shows  in  mental  and  physical  depression  and 
tiredness. 

Hypnotic  measures  include  drugs,  hot  baths,  the  establishment 
of  proper  conditions  for  sleeping,  etc.  They  promote  sleep  either 
by  lessening  cerebral  congestion,  by  producing  cerebral  anemia, 
or  by  directly  depressing  the  cerebral  cells.  The  hypnotic  drugs 
act  essentially  in  the  last  way,  the  sleep  being  the  result  of  di- 
minished mental  activity  and  restlessness,  and  dulling  of  the  per- 
ceptions. In  other  words,  hypnotic  drugs  are  narcotic.  Their 
action  resembles  somewhat  that  of  the  general  anesthestics,  but 
is  slower  in  its  onset,  less  powerful,  and  more  lasting,  and  is  not 
intended  to  produce  a  deep  stage  of  narcosis.  It  goes  without 
saying  that  the  drugs  suitable  for  use  as  hypnotics  must  be  capa- 
ble of  depressing  the  cerebrum  to  the  sleep  stage  without  any 
essential  depression  of  the  vital  medullary  centers.  All  hypnotics 
act  with  more  power  at  the  usual  sleep  time,  and  if  a  patient  is 
in  bed  in  a  quiet,  darkened  room.  In  fact,  if  the  patient  is  about 
and  active,  the  ordinary  dose  of  a  hypnotic  may  scarcely  produce 
even  drowsiness. 

Because  of  the  peculiar  nature  of  insomnia,  the  taking  of 
hypnotic  drugs  may  in  many  cases  lead  to  a  drug  habit.  On  this 
account  a  physician  should  avoid,  if  possible,  the  repeated  ad- 
ministration of  hypnotics  for  long  periods,  especially  with  neu- 
rotic patients,  and  should  endeavor  to  keep  the  drug-taking  under 
his  own  control.  If  a  hypnotic  drug  seems  imperative,  the  pre- 
scription should  be  changed  from  time  to  time;  but  it  is  often 
possible,  by  very  simple  measures,  to  improve  the  patient's  sleep- 
ing tendencies,  and  so  escape  the  necessity  for  the  use  of  drugs. 


358  PHARMACOLOGY   AND   THERAPEUTICS 

Some  simple  hypnotic  measures  are: 

1.  Avoidance  of  conditions  that  promote  wakefulness,  such 

as  noisy  or  disturbing  surroundings,  active  mental  work 
just  before  going  to  bed,  exciting  plays,  emotional  music, 
or  caffeine  drinks  in  the  evening. 

2.  Establishment  of  conditions  that  favor  mental  relaxation 

and  sleepiness,  such  as  a  walk  in  the  open  air  in  the  even- 
ing or  a  hot  bath.  If  there  seems  to  be  a  psychic  demand 
for  some  drug,  but  no  physical  demand,  a  harmless 
remedy,  such  as  sugar  of  milk  in  capsules,  tablet  tritu- 
rates or  pills  (prescribed  as  'Til.  Blank"),  or  a  bitterish 
dose  by  mouth,  or  a  hypodermic  of  plain  water  (thought 
by  the  patient  to  be  morphine)  may  be  effective. 
There  are  three  types  or  degrees  of  cerebral  depression  which 
may  be  desired  from  hypnotic  drugs. 

1.  Brief,  mild  depression — to  induce  the  onset  of  sleep  only, 

the  sleep  then  tending  normally  to  continue  for  the  usual 
length  of  time;  a  glass  of  ale,  for  example,  when  a  person 
is  fatigued  but  cannot  get  to  sleep  because  of  excitement, 
mental  activity,  or  restlessness. 

2.  Prolonged  mild  depression — both  to  induce  sleep  and  to 

maintain  it  for  a  length  of  time,  when  the  normal  tend- 
ency to  sleep  seems  to  be  absent,  or  when  the  perceptive 
faculties  are  overkeen  so  that  waking  is  easy,  as  in 
fevers,  neurasthenia,  various  neuroses,  some  forms  of 
habitual  insomnia,  etc.  An  occasional  drug  for  this 
purpose  might  be  chloral  hydrate  or  veronal. 

3.  Prolonged  depression  -with  analgesia — to  produce  and  main- 

tain quiet  and  sleep,  in  spite  of  pain  or  other  powerful 
factors  .which  tend  to  keep  the  patient  awake,  e.  g., 
morphine.  Drugs  which  abolish  pain  are  "analgesic." 

A  hypnotic  must  be  considered  as  to  its  effectiveness,  its 
rapidity  of  action,  its  length  of  action,  its  power  to  overcome 
pain,  and  its  safety.  We  might,  for  practical  purposes,  divide 
the  hypnotics  in  common  use  into — (a)  Those  which  do  not  abol- 
ish pain,  as  chloral  hydrate,  (b)  Those  which  do  abolish  pain, 
as  morphine. 

A.  Hypnotics   Which    Do   Not   Abolish   Pain 

CHLORAL  HYDRATE 

Chloralum  hydralum,  or  hydrated  chloral,  CCl.jCOH  +  H2O,  is 
prepared  by  passing  chlorine  gas  through  absolute  alcohol  and 
precipitating  by  water.  It  occurs  in  the  form  of  hygroscopic 


CHLORAL   HYDRATE  359 

crystals  with  bitter,  caustic  taste  and  penetrating  odor.  It  is 
freely  soluble  in  water,  alcohol,  ether,  chloroform,  and  the  fixed 
and  volatile  oils,  and  liquefies  when  mixed  with  camphor,  men- 
thol, or  thymol.  In  strongly  alkaline  liquids  it  is  decomposed, 
chloroform  being  set  free;  but  in  a  strength  of  carbonated  alkali 
the  same  as  that  of  the  blood  it  remains  unchanged.  The  dose  is 
1 5  grains  ( i  gm.) .  There  are  no  preparations  except  the  National 
Formulary  liquid,  chloral-camphor,  made  by  mixing  equal  parts 
of  chloral  and  camphor,  and  used  externally  as  a  counterirritant. 

Pharmacologic  Action. — Microorganisms. — Having  some  an- 
tiseptic power,  it  is  sometimes  added  to  urine  as  a  preservative. 

External.—  Applied  to  the  skin  it  is  counterirritant,  producing 
reddening  and  warmth ;  there  is  slight  local  anesthesia  from  depres- 
sion of  the  ends  of  the  sensory  nerves.  If  applied  continuously 
in  concentrated  form,  it  will  produce  death  of  tissue,  with  slough- 
ing and  the  formation  of  an  ulcer.  This  is  because  of  its  contained 
chlorine,  which  gives  it  an  especially  destructive  action  upon 
protoplasm. 

Alimentary  Tract. — The  taste  is  characteristic  and  unpleasant. 
Small  doses  are  carminative,  but  doses  large  enough  for  hypnotic 
effects  are  irritant,  and  unless  well  diluted  may  induce  nausea  and 
even  vomiting. 

A  bsorption  is  fairly  rapid  from  the  stomach  and  intestines. 

Nervous  System. — In  hypnotic  doses  chloral  hydrate  fairly  rap- 
idly induces  a  mild  but  prolonged  cerebral  depression,  accom- 
panied by  the  phenomena  of  natural  sleep.  It  is  a  very  reliable 
hypnotic.  The  pulse  and  respiration  are  somewhat  slowed,  the 
pupil  is  in  midcontraction,  the  CO2  of  the  blood  is  reduced  as  in 
sleep,  and  the  patient  may  be  fairly  easily  aroused  by  noises  or 
pain  or  other  sleep  antagonists. 

From  therapeutic  amounts  there  is  no  essential  analgesia,  so 
that  pain  is  not  abolished,  and  in  animal  experiments  it  is  found 
that  there  must  be  profound  narcosis  before  there  is  any  per- 
ceptible diminution  in  the  response  to  painful  stimuli.  The  re- 
flexes are  somewhat  depressed,  but  not  enough  by  safe  amounts 
to  make  the  drug  more  than  weakly  antidotal  to  the  convulsions 
of  eclampsia,  tetanus,  and  strychnine-poisoning.  In  dogs  chloral 
is  antidotal  to  strychnine,  for  dogs  can  take  a  much  larger  dose 
of  chloral  without  dangerous  depression.  Pringard  gave  0.25 
gm.  and  Hopkins  1.5  gm.  per  kilo  without  death. 

From  poisonous  doses  there  is  profound  stupor,  diminished 
excitability  of  the  motor  areas  of  the  brain,  as  shown  in  experi- 
ments with  dogs,  depressed  pain  sense,  and  diminished  reflexes, 
so  that  there  is  more  or  less  muscular  relaxation.  The  patient 
passes  through  stages  similar  to  those  from  chloroform,  and 


360  PHARMACOLOGY   AND   THERAPEUTICS 

may  pass  to  a  state  of  surgical  anesthesia  (coma),  with  abolition 
of  consciousness  and  of  the  reflexes,  but  in  imminent  danger  of 
collapse. 

The  peripheral  nerves  are  not  affected  by  systemic  administra- 
tion. From  local  application  there  is  slight  depression  of  the 
sensory  nerve-endings.  (See  Local  Action.) 

Respiration. — In  the  sleep  produced  by  therapeutic  doses  the 
breathing  is  slowed  as  in  ordinary  sleep  and  the  response  to  CO2 
is  normal;  while  from  poisonous  doses,  through  depression  of  the 
respiratory  center  and  the  failure  of  the  circulation,  the  breathing 
becomes  slow  and  shallow.  Death  takes  place  usually  from  failure 
of  the  respiration,  but  restoration  by  artificial  respiration  is  im- 
possible because  of  the  feeble  circulation. 

Circulation. — The  addition  of  chloral  hydrate  to  the  fluid 
used  in  perfusing  an  isolated  heart  induces  a  few  strengthened 
beats,  presumably  from  protoplasmic  irritation,  and  then  a  slow- 
ing of  the  heart,  with  gradually  weakening  contraction  in  systole 
and  increasing  relaxation  in  diastole.  The  heart  loses  its  tone 
and  its  contractility,  and  soon  stops  with  the  ventricles  widely 
dilated  in  diastole.  These  effects  are  due  to  direct  depression  of 
the  muscle. 

On  measuring  the  outflow  of  a  perfused  viscus  or  severed  limb, 
the  addition  of  a  solution  of  chloral  hydrate  causes  a  momentary 
diminution  of  outflow,  showing  contraction  of  the  arteries,  but 
this  is  followed  quickly  and  persistently  by  an  increased  outflow, 
so  that  the  essential  peripheral  action  is  dilatation  of  the  arteries. 
This  is  brought  about  by  a  direct  depression  of  the  arterial  mus- 
cles. In  the  intact  animal  a  large  dose  also  depresses  the  vaso- 
constrictor center. 

Chloral  hydrate,  therefore,  in  good-sized  dose  is  a  circulatory 
depressant,  acting  most  strikingly  to  depress  the  heart  muscle, 
but  also  to  depress  the  vasoconstrictor  center  and  the  muscles  of 
the  arteries.  The  vagus  center  is  also  depressed,  but  in  spite  of 
this  the  heart  is  slowed  from  muscular  weakening. 

In  the  sleep  from  a  single  safe  hypnotic  dose  it  is  observed  that 
the  slowing  of  the  heart  and  the  lowering  of  blood-pressure  are 
not  any  greater  than  those  in  ordinary  sleep.,  i.  c.,  the  circulatory 
depression  is  not  manifest;  while  with  only  slightly  larger  than 
ordinary  therapeutic  doses  the  circulatory  depression  may  super- 
vene, so  that  the  drug  becomes  distinctly  dangerous.  Archan- 
gelsky  found  that  the  blood  of  a  dog  in  deep  chloral  sleep  con- 
tained 0.03-0.05  per  cent,  of  chloral  hydrate,  that  at  0.056  per 
cent,  the  arterial  pressure  had  fallen  to  one-half,  and  at  0.07  per 
cent,  the  breathing  stopped.  There  are  reports  of  death  from 
only  double  the  dose  to  which  the  patient  or  habitue  had  been 


CHLORAL   HYDRATE  361 

accustomed.  Hence  the  margin  of  safety  with  chloral  is  a  narrow 
one. 

When  taken  at  regular  intervals  for  a  long  period  chloral 
tends  to  lessen  the  viscosity  of  the  blood,  to  destroy  the  red  and 
white  blood-corpuscles,  and  to  cause  fatty  degeneration  in  heart 
and  arteries.  Even  small  doses  cause  dilatation  of  the  cutaneous 
arterioles,  with  flushing  of  the  skin. 

Temperature. — On  account  of  diminished  activity  there  is 
lessened  production  of  heat,  and  on  account  of  the  dilatation  of  the 
cutaneous  vessels  there  is  increased  dissipation  of  heat,  so  chloral 
tends  to  lower  temperature.  It  is  not,  however,  employed  as  an 
antipyretic.  A  subnormal  temperature  is  seen  in  poisoning. 

Elimination. — When  warmed  with  strong  alkalies  in  a  test- 
tube  chloral  readily  liberates  chloroform,  yet  in  a  solution  of 
sodium  carbonate  of  the  strength  in  the  blood  it  does  not  de- 
compose at  the  temperature  of  the  body;  and  it  does  not  liberate 
chloroform  in  the  blood,  for  none  has  been  found  either  in  the 
blood  or  in  the  breath  (Hammarsten,  etc.).  Instead  of  this  the 
chloral,  which  is  trichloraldehyd,  becomes  trichlorethyl-alcohol, 
and  combines  with  glycuronic  acid  to  form  the  non-toxic  uro- 
chloralic  acid  (trichlorethyl-glycuronic  acid).  This  is  excreted 
slightly  by  the  stomach,  but  mostly  by  the  kidneys.  A  small 
amount  of  chloral  may  be  excreted  unchanged.  In  the  urine, 
urochloralic  acid  is  said  to  give  a  reaction  with  Fehling's  solution 
similar  to  that  of  glucose,  but  in  a  large  number  of  tests  of  the 
urine  from  patients  taking  from  10  to  1 20  grains  of  chloral  hydrate 
a  day  the  writer  was  unable  to  get  a  single  reduction  of  the  Feh- 
ling's, except  after  boiling  for  a  minute  or  two.  The  reducing 
substance  is  readily  distinguished  from  dextrose,  as  it  turns  the 
plane  of  polarized  light  to  the  left  and  does  not  ferment  with  yeast. 

Metabolism. — Chloral  hydrate,  chloroform,  and  other  chlorine- 
containing  bodies  of  the  methane  group  are  marked  protoplasm 
poisons;  and  after  chloral  there  is  evidence  of  increased  protein 
destruction,  with  the  appearance  in  the  urine  of  increased  ni- 
trogen, phosphorus,  and  sulphur,  the  destructive  products  being 
less  completely  oxidized  than  normally.  The  effects  are  much 
less  pronounced  than  from  chloroform.  There  is  a  slight  tendency 
to  fatty  degeneration  in  the  liver,  heart,  and  arteries,  especially 
in  chronic  chloral  takers. 

In  a  study  of  the  effects  on  metabolism  J.  G.  Hopkins  (IQII) 
gave  dogs  as  much  as  1.5  gm.  per  kilo  as  the  daily  dose,  enough 
to  produce  profound  narcosis  and  anesthesia.  He  found  no  areas 
of  necrosis  and  only  occasional  very  slight  fatty  changes  in  the 
liver,  of  the  type  produced  by  chloroform,  and  no  changes  at  all 
in  the  kidneys. 


362  PHARMACOLOGY   AND   THERAPEUTICS 

Uterus. — Chloral  is  said  to  promote  relaxation  of  the  cervix 
in  the  first  stage  of  labor,  without  very  greatly  lessening  the 
normal  uterine  contractions. 

Untoward  Effects. — Occasionally,  owing  to  idiosyncrasy,  a 
hypnotic  dose  results  in  excitement  and  headache  instead  of 
sleep;  or  in  a  skin  rash  of  the  types  of  erythema,  urticaria,  pur- 
pura,  and  bullae;  or  in  temporary  gastro-intestinal  disturbances. 

Toxicology. — Acute  Poisoning. — The  condition  is  one  of  pro- 
found narcosis,  with  diminution  or  abolition  of  the  reflexes, 
muscular  relaxation,  and  early  and  marked  respiratory  and  cir- 
culatory depression.  It  may  be  distinguished  from  morphine 
poisoning  by  the  absence  of  very  slow  respiration  and  by  the 
circulatory  depression,  the  muscular  relaxation,  the  marked 
diminution  or  abolition  of  the  reflexes,  and  the  pupil  in  midcon- 
traction.  The  many  cases  reported  of  collapse  from  very  little 
above  the  hypnotic  dose  show  that  the  drug  is  a  dangerous  one. 
Death  has  resulted  from  i  dram  (4  gm.)  given  at  one  dose,  though 
2  or  3  drams  (8-12  gm.)  have  been  taken  in  twenty-four  hours 
without  apparent  toxic  effects.  Amounts  of  720  grains  (45  gm.) 
in  forty-two  hours  (Geis),  and  640  grains  (41  gm.)  in  three  days 
(Rogers),  have  been  recovered  from.  The  treatment  is  that  for 
collapse  and  central  depression,  the  preferred  drugs  being  caffeine, 
atropine,  strychnine,  and  camphor.  Artificial  respiration,  oxygen, 
and  other  measures  may  be  employed.  Excretion  may  be  pro- 
moted by  saline  infusion  or  abundant  alkali- water  therapy.  The 
greatest  care  is  necessary  to  avoid  exertion  on  the  part  of  the 
patient,  as  this  tends  to  precipitate  heart  failure. 

Chronic  Poisoning  or  Chloralism. — The  chloral  habit  is  not 
uncommon,  especially  among  neurotic  persons  and  brain- workers, 
The  pronounced  habitue  becomes  thin  and  anemic,  has  gastric 
disturbances,  loss  of  appetite,  constipation,  mental  depression, 
lack  of  energy,  weakened  will  power,  and  various  nervous  symp- 
toms. Skin  eruptions  may  appear,  and  there  is  a  possibility  of 
fatty  degeneration  of  heart,  arteries,  liver,  and  kidneys.  The 
treatment  is  to  withdraw  the  drug  slowly,  to  administer  alkalies 
in  large  quantity,  to  give  wholesome  food,  especially  carbohy- 
drates, and  to  place  the  patient  in  hygienic  conditions  of  living. 

Tolerance  is  but  slowly  established,  and  the  nightly  dose  may 
not  require  increasing  for  a  long  time. 

Therapeutics. — Externally,  chloral-camphor  is  employed  as  a 
counterirritant  and  local  analgesic  in  muscular  and  neuralgic  pains 
and  toothache. 

Systemically. — i.  As  a  hypnotic — in  fever,  in  various  forms 
of  delirium,  or  in  conditions  of  nervousness  or  restlessness  from 
overwork  or  excesses,  e.  g.,  alcoholic  or  sexual.  It  is  a  powerful 


CHLORAL   HYDRATE  363 

and  reliable  sleep-producer  in  dose  of  10  to  30  grains  (0.7-2  gm.). 
The  beginning  dose  should  not  ordinarily  exceed  this. 

2.  As  a  circulatory  depressant — in  cases  with  high  arterial 
tension,  as  in  chronic  nephritis  or  arteriosclerosis.     Its  action 
may  be  due  to  its  effect  upon  the  viscosity  of  the  blood,  but  it  is 
probably  of  very  little  real  use.     Dose,  5  to  10  grains  (0.3-0.7  gm.) 
three  or  four  times  a  day. 

3.  In  obstetrics;  when  the  first  stage  is  prolonged,  a  dose  of 
30  grains  (2  gm.),  by  mouth  or  rectum,  may  give  the  patient  rest 
and  promote  relaxation  of  the  cervix. 

Chloral  has  some  employment  as  a  motor  depressant  in  cer- 
tain spasmodic  conditions,  such  as  whooping-cough,  chorea,  spas- 
modic asthma,  tetanus,  eclampsia,  and  strychnine-poisoning,  but 
for  an  effect  in  these  cases  larger  than  safe  doses  are  required.  It 
is  of  no  value  to  check  pain. 

Cautions  or  Contraindications. — i.  Failure  or  threatened  fail- 
ure of  the  circulation. 

2.  Depressed  states  of  the  respiration,  as  in  pneumonia  and 
uremia. 

3.  Acute  nephritis. 

4.  Acute  gastritis  and  conditions  of  stomach  irritation. 
Administration. — In  aqueous  solution,  well  diluted,  often  with 

the  addition  of  bromides.  It  should  never  be  given  with  alcohol 
(whisky,  elixirs,  etc.),  as  the  chloral  alcoholate  formed  is  rapidly 
depressing  to  the  cerebrum  and  medulla  and  constitutes  the 
notorious  "knock-out  drops." 

Butyl  chloral  hydrate  is  sometimes  employed  for  trifacial 
neuralgia  in  dose  of  5  grains  (0.3  gm.). 

Chloralformamidum  (chloralamide)  (CC1,3COH.HCONH2)  is 
a  crystalline  compound  of  chloral  and  formamide  (HCONH2), 
which  splits  into  its  components  in  the  blood.  Its  hypnotic  ac- 
tion, therefore,  results  from  chloral,  but  the  formamide  is  believed 
to  render  it  less  depressing  to  the  heart  and  vasoconstrictor  center. 
In  spite  of  the  formamide,  however,  the  chloral  set  free  has  its 
usual  metabolic  effects.  Chloralamide  is  soluble  in  18.7  parts  of 
water  and  1.3  of  alcohol.  Heated  with  water  to  60°  C.  (140°  F.), 
it  is  separated  into  its  components.  The  dose  for  mild  hypnosis 
is  15  to  30  grains,  administered  in  capsule,  cachet,  or  powder,  or 
in  hot  whisky.  An  elixir  is  on  the  market.  It  does  not  form 
knock-out  drops. 

Chloretone,  chlor-butanol,  or  chloroform-acetone,  CCl.jC.- 
(CH^o.OH,  is  a  compound  of  acetone  and  chloroform.  It  is  a 
white  powder,  soluble  in  hot  water,  alcohol,  glycerin,  and  the 
fixed  and  volatile  oils.  It  is  somewhat  antiseptic,  and  is  used  as 
a  preservative  in  solutions  of  adrenaline  and  other  unstable  bodies. 


364  PHARMACOLOGY  AND  THERAPEUTICS 

Its  solutions  are  not  absorbed  by  the  unbroken  skin,  but  are  ab- 
sorbed by  mucous  membranes  and  raw  surfaces,  and  are  locally 
somewhat  anesthetic,  depressing  the  ends  of  the  sensory  nerves. 
On  this  account  it  may  be  used  in  solution  or  powder  as  an  anti- 
septic, analgesic  application  to  ulcers,  as  of  the  leg  or  stomach,  or 
in  tuberculous  laryngitis  or  in  a  decayed  tooth.  In  seasickness 
it  acts  both  locally  in  the  stomach,  to  lessen  nausea  and  vomiting, 
and  as  a  central  sedative.  -  Systemically  it  depresses  the  cere- 
brum, producing  quiet  and  sleep.  But  it  is  a  much  less  powerful 
hypnotic  than  chloral,  and  is  said  to  be  not  without  danger  in  the 
larger  doses.  It  has  been  recommended  for  its  narcotic  value  as 
a  preliminary  to  ether  anesthesia.  Dose,  15  grains  (i  gm.). 

In  the  laboratory  it  is  employed  to  anesthetize  small  animals, 
such  as  rabbits,  but  a  systemic  effect  sufficient  to  abolish  pain 
cannot  be  elicited  in  man  without  danger. 

ETHYLATED  COMPOUNDS 

In  experimental  chemistry  it  has  been  found  that  the  intro- 
duction of  the  radicle  ethyl,  C2H5,into  an  organic  chemical  will  fre- 
quently confer  upon  it  a  sedative  action.  Hence  many  synthetic 
hypnotics  containing  ethyl  groups  have  been  placed  upon  the 
market.  Ether  is  ethyl  oxide,  and  common  grain  alcohol  is  ethyl 
alcohol.  The  more  commonly  employed  ethylated  hypnotics  are: 

Sulfonal  (sulphonmethanum),  (CH3)2C.  (SO2C2H5)2,  a  di-ethyl 

H3Cx        /SO2C2Hs 
compound,          ;C<  .  and   its  tri-ethyl   congener,  trional 

HsC-7    xS02CoH5 

(sulphonethylmethanum),  CH3.C2H5.C(SO2C2H5)2,  are  crystalline 
bodies  that  are  soluble  with  difficulty  in  water.  Trional  is  readily 
soluble  in  whisky  or  alcohol.  Dose,  15  grains  (i  gm.).  These 
drugs  are  similar  in  effects,  but  differ  in  their  rate  of  absorption 
and  their  rapidity  of  action.  Trional  is  the  more  rapidly  ab- 
sorbed, and  being  more  highly  ethylated,  is  prompter  and  more 
certain  in  its  sedative  effects.  They  both  induce  quiet  and  sleep 
without  any  depression  of  heart  or  medullary  centers,  but  they  do 
not  allay  pain.  They  have  been  used  to  check  nausea,  as  in 
seasickness.  They  are  eliminated  as  ethyl  sulphonates,  sulfonal 
tending  to  be  so  slowly  excreted  that  drowsiness  may  persist 
the  following  day.  They  are  usually  administered  in  capsules, 
or  with  hot  milk  or  whisky,  sulfonal  being  given  two  or  three 
hours,  and  trional  one-half  to  one  hour,  before  the  expected  sleep. 
The  larger  doses  are  said  to  be  irritant  to  both  stomach  and  kid- 
neys. Dreams  and  nightmares  and  herpetic  ulcers  of  the  mouth 
are  untoward  effects  attributed  to  trional. 

Poisoning  has  occurred  a  number  of  times  from  their  excessive 


ETHYLATED    COMPOUNDS  365 

use  by  the  laity,  in  amounts,  for  example,  of  200  grains  (13  gm.)  of 
sulfonal  or  120  grains  (8  gm.)  of  trional.  The  symptoms  are 
chiefly  gastric,  renal,  and  mental.  They  are:  nausea,  vomiting, 
diarrhea,  and  abdominal  pain,  with  stupor,  mental  confusion, 
hallucinations,  muscular  weakness,  and  incoordination,  followed 
by  collapse  and  death.  Rolleston  reports  collapse  with  uncon- 
sciousness, very  weak  pulse,  and  slow  breathing  from  125  grains 
of  trional.  In  some  cases,  though  not  in  all,  the  urine  contains 
hematoporphyrin  from  destruction  of  red  blood-cells.  It  may 
contain  albumin  and  casts  or  blood  from  acute  nephritis,  or  it 
may  be  suppressed.  Von  Noorden  has  advised  against  the  use 
of  these  drugs  in  nephritis  because  of  their  tendency  to  irritate 
the  renal  epithelium.  Starr  mentions  them  as  causes  of  multiple 
neuritis.  The  poisoning  is  treated  by  large  quantities  of  milk, 
and  alkalies  such  as  sodium  bicarbonate.  The  alkali  is  to 
combat  acidosis. 

Veronal,  di-ethyl  malonyl  urea,  di-ethyl  barbituric  acid, 
C(C2H5)2.CO(CONH)2,  slightly  bitter  and  slightly  soluble  in 
water  (i  :  150),  has  an  action  resembling  that  of  trional.  It  usu- 
ally results  in  sleep  in  one-half  to  one  hour,  and  this  lasts  several 
hours,  without  depression  of  the  circulation.  Veronal  may, 
however,  be  very  slowly  excreted,  so  that  drowsiness,  headache, 
and  dizziness  persist  all  through  the  following  day.  In  some  cases 
the  sleep  is  dreamy,  unref reshing ;  and  at  times,  particularly  in 
old  people,  sleep  persists  for  twenty-four  to  thirty-six  hours. 
It  is  extensively  employed  as  a  hypnotic  in  all  ordinary  con- 
ditions where  sleep  is  wanting.  It  is  also  used  to  some  extent 
in  epilepsy,  delirium  tremens,  prolonged  labor,  and  the  vomiting 
of  pregnancy  and  seasickness.  Dose,  5  grains  (0.3  gm.).  A  sodium 
compound  of  veronal,  soluble  in  5  parts  of  water,  has  been 
marketed  under  the  names  Medinal  and  Veronal-sodium.  It  is 
bitter,  but  may  be  used  by  rectum,  or  even  in  10  per  cent,  solution, 
hypodermatically.  Luminal  is  a  close  relative. 

Toxicology. — Itching  of  the  skin,  erythema  and  other  skin 
rashes,  conjunctivitis,  and  glycosuria  have  been  reported  follow- 
ing its  use.  Jacobi  says  that  in  addition  to  the  hypnotic  ac- 
tion it  causes  relaxation  of  the  capillary  walls  similar  to  that  from 
arsenic,  with  fall  in  blood-pressure,  congestion  of  the  abdominal 
viscera,  and  depression  of  respiration.  It  does  not  affect  the 
cardiac  muscle.  From  20  grains  (1.3  gm.)  given  one  night 
and  10  grains  (0.7  gm.)  the  following  night,  the  author  saw  a 
case  develop  a  generalized  enlargement  of  the  lymph-nodes,  a 
measles  type  of  rash,  and  fever  up  to  103°  F.  which  lasted  a  week. 
The  diagnosis  was  established  by  the  recurrence  of  these  symp- 
toms for  three  days  on  two  occasions  following  10  grains  (0.7  gm.) 


366  PHARMACOLOGY   AND   THERAPEUTICS 

of  medinal.  The  average  lethal  dose  is  8  to  10  gm.  Several 
deaths  have  been  reported,  as  in  a  child  of  three  years  after 
10  grains  (0.7  gm.).  The  treatment  consists  of  alkalies  and 
diuresis,  and  that  for  collapse. 

Bromural,  monobrom-valeryl-urea,  (CH3)2CH.CHBr.CONH.- 
CO.NH2.,  resembles  veronal  very  closely  in  its  effects  but  is  less 
active.  Dose,  15  grains  (i  gm.).  Isopral  is  a  similar  drug  with 
the  same  dose. 

Adalin,  brom-di-ethyl-acetyl-carbamide,  C(C2H5)2Br.CONH.- 
CONH2,  is  a  substance  of  the  same  class  as  veronal  and  bro- 
mural.  It  is  soluble  freely  in  alcohol,  but  with  difficulty  in 
water,  is  almost  tasteless,  and  is  milder  in  action  than  veronal. 
Dose,  15  grains  (i  gm.).  A  case  is  reported  of  sixty  hours' 
unconsciousness  after  45  grains  (3  gm.). 

Urethane,  oethylis  carbamas,  NH2COOC2H5,  soluble  in  less 
than  its  own  weight  of  water,  is  a  mild  hypnotic  and  diuretic  in 
dose  of  i  dram  (4  gm.).  It  changes  in  the  body  to  urea,  and 
because  of  this  fact  is  advised  against  in  nephritis. 

Hedonal  is  methyl-propyl-carbinol-urethane,  soluble  in  120 
parts  of  water  and  readily  in  alcohol.  It  is  incompatible  with 
alkalies.  Dose,  15  grains  (i  gm.).  It  has  been  used  as  an  in- 
travenous anesthetic,  Fedoroff  (1910)  reporting  330  cases.  Page 
(1912)  recommends  a  solution  of  0.75  per  cent,  in  normal  saline 
infused  at  the  rate  of  50  to  150  c.c.  per  minute.  The  adult  dose 
is  500  c.c.  The  respiration  was  deep  and  regular,  the  pulse  good, 
the  reflexes  were  abolished.  Veale  (1912)  employed  it  in  quan- 
tities up  to  1200  c.c.  and  from  the  larger  amounts  got  skin  edema, 
pulmonary  edema,  bronchitis,  and  pneumonia,  as  well  as  throm- 
bosis in  the  vein. 

Amylene  hydrate,  dimethyl-ethyl  carbinol,  (CH,3)2COHC2H5, 
a  limpid  liquid,  soluble  in  10  parts  of  water,  resembles  paral- 
dchyd  in  its  action,  but  is  a  milder  hypnotic  and  less  disagree- 
able in  odor  and  taste.  Dose,  i  dram  (4  c.c.)  by  mouth  or  rectum. 
A  compound  of  amylene  with  chloral  is  known  as  "dormiol." 

All  the  above  are  the  hypnotics  which  are  in  common  use 
to  induce  sleep  where  the  wakefulness  is  not  due  to  pain.  Ex- 
cept chloral  hydrate,  which  is  powerful  and  dangerous,  none 
of  these,  unless  in  doses  above  the  ordinary,  cause  any  essential 
depression  of  the  heart,  medullary  centers,  or  reflexes;  they  are, 
therefore,  safe  general  hypnotics  which  can  be  employed  even 
in  depressed  states  of  the  circulation. 


Paraldehyd  (CH3COH)8  is  not  an  ethylated  compound,  but 
may  be  considered  here.     It  is  a  volatile  liquid  with  a  penetrating, 


BROMIDES  367 

disagreeable  ethereal  odor  and  a  burning  taste.  It  is  soluble  in 
8  parts  of  water,  and  freely  in  alcohol  and  the  oils.  Locally  it 
resembles  ether,  and  by  its  irritation  of  the  mouth  and  probably 
also  of  the  stomach  is  a  reflex  stimulant  of  the  respiration  and 
circulation.  It  is  rapidly  absorbed,  and  soon  produces  sleep 
without  any  appreciable  depression  of  the  medullary  centers. 
The  chief  drawbacks  to  its  use  are  its  unpleasant  taste,  its  irri- 
tant local  effects,  and  the  persistence  of  its  odor  and  its  taste, 
owing  to  eructations  from  the  stomach  or  to  its  excretion  in  the 
breath.  It  may  be  administered  dissolved  in  sweetened  water, 
syrup  of  lemon,  lemonade,  whisky,  or  beer,  which  partly  disguise 
the  taste.  It  may  also  be  given  by  rectum,  dissolved  in  water. 
Dose,  30  minims  (2  c.c.)  for  ordinary  hypnotic  effects.  In  the 
insomnia  or  delirium  of  alcoholics  it  is  sometimes  administered 
with  excellent  effect  in  doses  of  2  drams  to  |  ounce  (8  to  15  c.c.). 
We  have  seen  one  ounce  administered  in  three  hours  with  ap- 
parently nothing  but  good  effect.  Poisoning  results  in  stupor, 
with  depression  of  the  medullary  centers  and  heart  muscle,  and 
collapse.  Three  and  one-third  ounces  (100  c.c.)  at  one  dose  have 
been  recovered  from.  The  paraldehyd  habit  is  occasionally  met 
with.  Fonaca  and  Querelli  (1912)  record  the  case  of  a  physi- 
cian who  took  it  for  five  years,  the  nightly  dose  reaching  \  ounce 
(15  c.c.).  Then  symptoms  resembling  those  of  chronic  alcoholism 
were  followed  by  delirium  tremens  with  one  convulsion,  high 
temperature,  weak  pulse,  intense  sweating,  polyuria,  and  marked 
thirst.  Paraldehyd  has  been  employed  for  intravenous  anes- 
thesia. (See  page  307.) 

Hypnotics  Which  May  Be  Used  To  Abolish  Pain 

BROMIDES 

The  bromides  in  common  use  for  narcotic  effect  are  those  of 
potassium,  sodium,  and  ammonium,  and  to  a  small  extent  those 
of  lithium,  strontium,  and  calcium.  All  have  a  strongly  salty, 
bitterish  taste,  all  are  very  soluble  in  water,  and  all  except  potas- 
sium bromide  are  moderately  soluble  in  alcohol.  The  dose  de- 
pends on  the  desired  result.  For  nervousness  arid  restlessness  it 
is  10  to  30  grains  (0.7-2  gm.)  two  to  four  times  a  clay;  as  a 
hypnotic,  20  to  60  grains  (1.3-4  gm.) ;  for  epilepsy,  20  to  60  grains 
(1.3-4  gm.)  three  times  a  day.  L.  Pierce  Clark  reports  the  use  of 
400  grains  (27  gm.)  a  clay  for  live  days  in  epilepsy.  Diluted 
hydrobromic  acid  (10  per  cent.)  is  sometimes  used  as  a  bromide 
in  dose  of  i  dram  (4  c.c.).  In  equivalent  sedative  close  it  has  no 
advantage  over  the  alkaline  bromides,  and  is  strongly  acid. 


368  PHARMACOLOGY   AND   THERAPEUTICS 

Pharmacology. — Local. — Bromides  have  no  effect  upon  the 
unbroken  skin;  but  on  mucous  membranes  and  raw  tissues  they 
have  a  salt  action,  and  are  irritant  unless  well  diluted.  This 
irritation  is  followed  by  slight  anesthesia.  Before  the  use  of 
cocaine  their  solutions  were  painted  on  the  throat  as  mild 
anesthetics  to  favor  laryngeal  examination.  From  irritation  of 
the  stomach  they  sometimes  cause  nausea  and  vomiting. 

Absorption  is  fairly  rapid  from  stomach  and  intestines. 

Nervous  System. — On  the  whole  central  nervous  system  except 
the  medulla  there  is  a  moderate  but  lasting  general  depression 
which  can  be  maintained  day  after  day  for  long  periods,  with 
little,  if  any,  effect  upon  the  vital  medullary  centers. 

Cerebrum. — The  mind  is  less  alert,  the  special  senses  are  less 
keen,  the  sense  of  pain  is  diminished,  and  there  is  indifference  or 
lack  of  attention  to  what  is  going  on.  Large  doses  produce 
drowsiness,  and  if  the  dose  is  given  at  bedtime,  favor  the  onset  and 
maintenance  of  sleep;  but  even  enormous  doses  (400  grains  a 
day)  will  not  force  sleep  in  the  daytime,  when  the  patient  is  up 
and  about.  As  a  hypnotic,  the  drug  acts  rather  to  permit  sleep, 
as  when  the  patient  is  anxious,  worried,  or  nervous,  than  to  force 
it  by  marked  depression  of  the  cerebrum.  Ulrich  claims  that 
large  doses  will  banish  melancholia  and  the  depression  of  neuras- 
thenia. 

From  repeated  very  large  doses,  as  sometimes  used  in  epilepsy, 
the  patient  passes  into  a  condition  of  mental  and  physical  slug- 
gishness, with  defective  memory,  stupidity,  general  apathy,  and 
inferior  mental  power. 

The  motor  areas  of  the  cortex  are  depressed,  for  in  a  dog 
under  bromides  it  is  impossible  to  produce  a  convulsion  by  their 
stimulation.  In  man,  too,  voluntary  motion  is  sluggish,  and  the 
cerebral  convulsions  of  epilepsy  may  be  absolutely  prevented. 
These  cerebral  effects  are  directly  opposed  by  caffeine. 

Spinal  Cord. — If  a  toxic  dose  of  strychnine  is  given  to  a 
bromidized  dog,  a  reflex  response  to  a  stimulus  may  be  obtained, 
but  the  extensive  convulsive  response  which  would  result  from 
the  strychnine  alone  does  not  occur.  The  effect  of  bromide  is 
the  opposite  to  that  of  strychnine,  the  passage  of  impulses  from 
afferent  fibers  to  motor  areas  being  retarded.  There  is  some 
evidence  that  it  acts  on  the  same  part  of  the  cord  as  strychnine, 
i.  c.,  the  primary  sensory  synapses.  It  is,  therefore,  irrational  to 
administer  bromides  and  strychnine  together.  The  depression 
of  the  reflexes  makes  a  general  depression  of  muscular  tone 
throughout  the  body,  and  loss  or  depression  of  the  sexual  reflex, 
but  not  usually  the  bladder  reflex. 

Circulation. — Under  ordinary  conditions  there  is  no  essential 


Fig.  41. — Bromide  eruption  (Schamberg). 


I'ig.  42. — Pustulobullous  eruption,  resembling  small-pox,  from  the  ingestion  of 
bromides  (Schamberg). 


J 


BROMIDES  369 

effect  from  therapeutic  doses  upon  the  heart,  the  arteries,  or  the 
nervous  mechanisms  of  control.  But  in  the  cardiac  neuroses, 
palpitation,  tachycardia,  etc.,  and  when  the  heart  is  overacting, 
as  from  general  nervousness,  the  effect  of  a  bromide  may  be  to 
steady  and  quiet  the  beat  by  its  general  sedative  effect  upon  the 
patient.  By  enormous  doses  the  muscles  of  the  heart  and  arteries 
and  the  vasoconstrictor  center  are  depressed  and  arterial  pressure 
falls.  In  large  amounts  the  potassium  ion  is  distinctly  depressing 
to  the  heart  muscle;  hence  potassium  bromide  in  the  large  doses 
tends  to  be  more  depressing  than  the  other  salts.  Greene  and 
Kruse  found  by  perfusion  experiments  that  in  physiologic  bal- 
anced solutions  bromides  are  relatively  non-toxic  to  heart 
muscle.  For  example,  a  bromide  Ringer's  solution  sustained  a 
frog's  heart  for  twenty-eight  hours.  But  if  bromides  are  used 
without  reference  to  isotonicity  the  base  (K,  Na,  Ca,  etc.)  becomes 
important. 

Respiratory. — Therapeutic  doses  have  no  effect  except  to 
diminish  the  coughing  reflex  and  lessen  the  tone  of  the  respiratory 
muscles.  Enormous  doses  somewhat  depress  the  center. 

Sexual  Organs. — Both  sexual  desire  and  sexual  power  are  di- 
minished through  cerebral  and  spinal  depression,  and  these 
effects  are  made  use  of  in  therapeutics. 

Elimination. — Bromides  are  excreted  chiefly  in  the  urine,  but 
somewhat  also  in  the  sweat,  in  mucous  secretions,  and  in  milk. 
Large  doses  given  to  a  nursing  mother  may  affect  the  infant.  The 
excretion  begins  very  quickly,  traces  being  found  in  the  urine  and 
saliva  in  a  few  minutes  after  ingestion.  But  a  part  of  the  bromide 
enters  the  body  fluids  and  protoplasm  and  replaces  some  of  the 
normal  sodium  chloride,  and  this  portion  is  but  slowly  excreted, 
so  that  bromide  may  be  found  in  the  urine  weeks  after  its  admin- 
istration has  been  stopped.  The  excretion  of  bromides  is  has- 
tened by  large  doses  of  sodium  chloride;  so  in  extreme  bromide 
administration,  as  in  some  epileptic  cases,  the  amount  of  chlorides 
is  reduced,  the  bromide  being  taken  with  the  food  in  the  place  of 
table  salt  (sodium  chloride).  Where  much  bromide  is  given  con- 
tinually, hydrobromic  acid  is  said  to  replace  some  of  the  hydro- 
chloric acid  of  the  gastric  juice. 

Skin  and  Mucous  Membranes. — Scattered  acne  pustules  very 
frequently  appear  on  the  face,  chest,  and  back;  more  rarely  the 
eruption  may  be  erythematous,  urticarial,  furuncular,  or  bullous. 
In  some  cases  extensive  superficial  ulceration  has  caused  serious 
symptoms.  Bromide  eruptions  have  been  mistaken  for  tertiary 
syphilitic  manifestations.  The  etiology  of  these  rashes  is  a  matter 
of  some  controversy.  It  has  been  suggested  that  the  gland 
mouths  are  irritated  by  an  accumulation  of  the  excreted  salt  as 

24 


370  PHARMACOLOGY   AND   THERAPEUTICS 

the  sweat  evaporates;  also  that  the  acid  of  the  sebaceous  secretion 
decomposes  the  bromide  and  sets  free  the  irritating  bromide.  But 
irritation  occurs  in  mucous  membranes  where  the  secretion  is 
alkaline,  and  no  excess  of  bromide  and  no  free  bromine  have  been 
found  in  washings  from  the  skin,  or  in  the  sweat  or  sebaceous 
secretions,  and  though  the  drug  is  reported  to  have  been  found 
a  few  times  in  the  sebaceous  glands,  most  investigators  have  not 
found  any  there  at  all.  But  better  evidence  than  any  other  that 
the  rash  is  not  due  to  gland  irritation  is  the  observation,  by  a 
number  of  careful  dermatopathologists  (Thin,  Colcott  Fox, 
Harris,  etc.),  that  the  changes  begin  in  the  papillary  layer  and 
not  necessarily  in  or  about  the  glands,  though  the  glands  may 
be  involved  secondarily. 

It  has  been  claimed  that  in  chronic  nephritis,  on  account  of 
obstruction  of  the  regular  channel  of  elimination,  the  rashes  are 
more  severe.  But  rashes  are  too  frequent  in  those  with  normal 
kidneys  to  allow  us  to  consider  diseased  kidneys  of  any  great  im- 
portance as  an  etiologic  factor,  though  they  may  have  to  do  with 
the  severity  of  the  dermal  reaction.  L.  Pierce  Glark  reports 
that  even  after  enormous  dosage  he  has  been  able  to  prevent  the 
eruption  by  daily  colon  irrigations.  That  the  nervous  system  is 
a  factor  is  held  by  some,  on  the  grounds  that  very  small  amounts 
are  sufficient  to  produce  a  rash  in  those  who  show  the  idiosyn- 
crasy, and  that  sometimes  in  these  same  persons  the  larger  doses 
produce  the  least  rash;  in  addition,  most  of  these  rashes  are  ac- 
companied by  vasomotor  disturbances.  On  the  theory  that  it 
is  due  to  the  elimination  of  toxic  products,  colon  irrigations  have 
been  advised,  also  large  closes  of  alkalies,  intestinal  antiseptics, 
arsenic,  and  potassium  bitartrate,  and,  in  addition,  special  clean- 
liness of  the  skin.  The  rash  of  the  face,  for  example,  is  said  to  be 
lessened  by  vigorous  washing.  Stelwagon  suggests  diuretics  and 
the  free  drinking  of  water,  or,  in  other  words,  the  promotion  of 
rapid  elimination.  He  states  that  sodium  bromide  is  less  likely 
to  produce  a  rash  than  the  potassium  salt. 

Kidneys. — There  is  no  special  effect  upon  the  kidneys,  except 
that  large  doses  with  plenty  of  water  act  like  other  diffusible 
salts  to  increase  the  excretion  of  urine. 

Toxicology. — Acute  poisoning  from  a  single  very  large  dose 
shows  in  profound  depression  and  apathy,  or  an  actual  stupor 
lasting  from  one  to  several  days,  with  slow  respiration  and  rather 
low  arterial  pressure.  Death  has  rarely,  if  ever,  resulted  from 
bromide  alone. 

Chronic  Poisoning  or  Bromism. — Following  repeated  large 
doses  of  bromide  the  patient  becomes  dull,  stupid,  indifferent,  the 
face  expressionless,  pale,  usually  bearing  scattered  pimples,  the 


BROMIDES  371 

eyes  heavy,  all  mental  processes  and  voluntary  movements  slug- 
gish (speaking  is  slow,  replies  to  questions  are  delayed,  walking 
is  deliberate),  the  memory  defective,  general  tone  less,  sexual 
desire  and  sexual  power  abolished,  and  there  are  loss  of  appetite, 
nausea,  constipation,  and  a  general  lowering  of  vitality  and  vigor. 
This  is  the  state  into  which  some  epileptics  are  brought  by  ex- 
cessive bromide  treatment;  and  it  is  nowadays  thought  better, 
except  in  refractory  cases,  to  take  some  risk  of  convulsions  rather 
than  to  bring  a  patient  into  such  a  hopeless  condition  of  useless- 
ness.  Many  epileptics  have  led  active  lives,  e.  g.,  Napoleon  I. 

Treatment  for  Acute  and  Chronic  Poisoning.- — Stop  the  drug, 
give  sodium  chloride  and  much  water  to  favor  elimination,  keep 
up  body  activity  and  body  nutrition,  and  counteract  the  central 
depression  with  strychnine  and  caffeine.  Ulrich  states  that 
pushing  the  sodium  chloride  will  positively  abolish  bromism. 

Therapeutics. — Bromides  have  their  chief  employment  as 
sedatives  in  hyperesthetic  states  of  the  nervous  system.  They 
may  also  be  employed  to  promote  sleep,  especially  when  wake- 
fulness  is  due  to  worry  or  excitement  or  to  moderate  pain,  as  in 
toothache  or  neuralgia. 

Some  of  their  every-day  uses  are: 

1.  To  lessen  nervous  irritability,  as  in  general  restlessness,  in 
exophthalmic  goiter,  and  in  the  gastric,  intestinal,  and  cardiac 
neuroses. 

2.  To  allay  pain  (as  of  neuralgia,  neuritis,  toothache,  etc., 
which  is  felt  keenly  because  of  a  hyperesthetic  nervous  state) . 

j.  To  check  vomiting  if  reflex  or  central,  as  in  seasickness,  and 
not  from  stomach  irritation.  It  is  sometimes  employed  in  the 
vomiting  of  pregnancy, 

4.  To  lessen  sexual  hyperesthesia,  as  in  nymphomania  and 
chordee,  and  following  operations  upon  the  penis  in  the  adult, 
as  circumcision. 

5.  To  prevent  convulsions,  as  those  of  epilepsy,  tetanus,  and 
strychnine  poisoning.     For  the  last,  doses  of  not  less  than  half  an 
ounce  by  mouth  or  rectum  may  be  employed.     It  acts  rather 
slowly. 

6.  To  check  spasmodic  nervous  a/eclions  of  striated  muscle, 
such  as  chorea,  whooping-cough,  persistent  hiccup,  laryngismus 
stridulus,  and  convulsive  tic. 

7.  .To  quiet  the  reflexes  (lessen  the  heightened  tone)  in  spastic 
conditions  due  to  lesions  of  the  motor  tract,  as  in   multiple 
sclerosis. 

8.  To  lessen  cardiac  excitability,  as  in  extrasystoles  and  par- 
oxysmal tachycardia — doses  of  2  to  3  drams  (8-12  gm.). 

Of  the  various  bromides,  the  potassium  and  sodium  salts,  in 


372  PHARMACOLOGY   AND   THERAPEUTICS 

ordinary  doses,  have  no  measurable  differences,  and  are  preferred 
to  the  others.  In  the  very  large  doses  the  potassium  radicle  may 
have  a  special  depressing  effect  upon  the  muscle  of  the  heart  and 
arteries.  The  belief  that  ammonium  bromide  is  less  depressing 
to  the  heart  than  sodium  bromide  is  not  justified.  (See  Am- 
monium Chloride.) 

Bromipin  is  a  combination  of  bromine  with  oil  of  sesame,  and 
may  be  given  in  the  form  of  an  emulsion.  It  is  said  to  be  free 
from  irritating  effects  upon  the  stomach,  and  is  sometimes  sub- 
stituted for  the  alkaline  bromides  when  there  is  gastric  irritability. 
It  is  of  two  strengths,  10  and  25  per  cent.,  and  the  dose  is  i  to  2 
drams  (4-8  c.c.)  made  into  an  emulsion.  In  epilepsy  Kothe  rec- 
ommends 75  grains  (5  gm.)  three  times  a  day,  increasing  up  to 
600  grains  (40  gm.). 

Bromoform  (CHBr3)  is  a  homologue  of  chloroform,  CHC13. 
It  is  a  heavy  liquid,  readily  soluble  in  alcohol,  very  slightly  soluble 
in  water,  and  sweet  to  the  taste.  It  is  very  limpid,  so  that  i 
minim  contains  about  5  or  6  drops.  Its  only  therapeutic  use  is  in 
the  treatment  of  whooping-cough.  The  dose,  3  drops,  or  |  minim 
(0.03  c.c.)  for  a  child  one  year  old,  or  5  minims  (0.3  c.c.)  for  an 
adult,  is  usually  given  suspended  in  syrup,  but  is  better  dissolved 
in  alcohol  or  oil.  Poisoning  has  occurred  a  number  of  times  from 
the  undissolved  bromoform  at  the  bottom  of  a  bottle,  so  it  should 
be  well  shaken  before  the  dose  is  poured  out.  Serious  narcosis 
and  collapse  are  reported  in  a  child  of  eighteen  months  from  a 
dose  of  8  drops. 

OPIUM 

Opium  is  the  ''concrete  milky  exudation  obtained  by  incising 
the  unripe  capsules  of  Pa  paver  somni/erum  (Fam.  Papaveraced), 
and  yielding,  in  its  normal  moist  condition,  not  less  than  9  per 
cent,  of  morphine."  It  is  simply  the  dried  milk-juice  which 
exudes  from  two  or  three  encircling  incisions  made  in  the  green 
poppy  capsules  of  the  common  poppy  as  grown  in  oriental  coun- 
tries. The  only  opium  that  meets  the  U.  S.  P.  requirements  is 
that  from  Asia  Minor,  known  as  Turkish,  or  Smyrna  opium.  That 
used  for  smoking  is  less  strong  and  comes  mostly  from  India  and 
China. 

Opium  is  expensive  and  is  much  adulterated  with  vegetable 
debris,  sand,  earth,  and  even  nails  and  bullets  to  increase  its 
weight.  It  is  of  a  gummy  consistence  from  much  moisture;  but 
when  the  moisture  is  driven  off  by  heat,  it  can  be  powdered  or 
granulated.  The  dried  opium  is  stronger  by  the  amount  of  water 
driven  off.  For  the  manufacture  of  all  the  official  preparations 
the  Pharmacopoeia  employs  dried  opium  in  the  form  of  powdered 


OPIUM  373 

opium  (opii  pulvis),  or  granulated  opium  (opium  granulatum), 
and  these  are  required  by  the  Pharmacopoeia  to  assay  from  12 
to  12.5  per  cent,  of  morphine. 

The  opium  alkaloids  are  about  20  or  more  in  number  and 
constitute  two  chemical  groups,  the  phenanthrene,  represented 
by  morphine  and  codeine,  and  the  oxyquinoline,  represented  by 
papaverine  and  narcotine.  They  exist  mostly  as  salts  of  meconic 
acid.  None  of  these  alkaloids  are  isolated  and  used  except  mor- 
phine, codeine,  narcotine,  and  papaverine. 

Besides  the  12  to  12.5  per  cent,  of  morphine,  the  dried  opium 
contains  0.5  to  1.5  per  cent,  of  codeine,  5  or  6  per  cent,  of  narco- 
tine (a  nauseating  principle),  and  the  other  alkaloids  in  small 
amounts.  It  contains  neither  starch  nor  tannic  acid,  and  the 
presence  of  these  would  indicate  adulteration. 

Preparations  and  Doses. — These  are  made  from  powdered 
opium  (opii  pulvis)  or  granulated  opium  (opium  granulatum), 
containing  12  to  12.5  per  cent,  of  morphine;  dose,  i  grain  (0.06 
gm.),  which  contains  |  grain  (0.008  gm.)  of  morphine. 

Deodorized  opium — of  same  strength  as  powdered  opium,  but 
with  the  narcotine  and  certain  disagreeable  odorous 
substances  removed  by  benzin. 

Extract,  containing  20  per  cent,  morphine.     It  is  an  aqueous 
extract,  therefore  contains  only  those  parts  of  the  opium 
that  are  soluble  in  water.     Dose,  f  grain  (0.045  gm-)- 
Poicdcr  of  ipecac  and  opium  (Dover's  powder),  10  per  cent. 

of  each.     Dose,  10  grains  (0.7  gm.). 

Tincture  (laudanum),  10  per  cent.,  and  the  deodorized  tincture, 
10  per  cent.  Dose  of  each,  10  minims  (0.7  c.c.)  containing 
|  grain  of  morphine. 

Camphorated  tincture  (paregoric),  4  :  1000.  Dose,  i  dram 
(4  c.c.)  =  opium,  j  grain  (0.015  gm.)  =  morphine,  -^  grain 
(0.002  gm.). 

Lead  and  Opium  Wash  (Lotio  Plumbi  et  Opii,  N.  F.)  is  made 
by  adding  the  tincture  of  opium,  52-5-  grains  (3.5  c.c.),  to  a 
solution  of  lead  acetate,  26  grains  (1.75  gm.),  in  water  suffi- 
cient to  make  the  total  measure  3^  ounces  (100  c.c.).  It 
is  an  irrational  mixture,  as  the  opium  principles  are  not 
absorbed;  its  action  is  that  of  a  lead  salt. 
Some  of  the  alkaloids  or  their  salts  are  also  employed,  viz.: 
Codeine — soluble  in  120  parts  of  water  and  in  2  of  alcohol; 
codeine  phosphate,  soluble  in  2.3  of  water  and  325  of  alcohol; 
codeine  sulphate,  soluble  in  30  of  water  and  1280  of  alcohol. 
The  pure  alkaloid  is  best  for  use  in  alcoholic  solution,  and  the 
phosphate  for  aqueous  solution,  as  in  hypodermic  adminis- 
tration. Dose,  ^  grain  (0.03  gm.). 


374  PHARMACOLOGY   AND   THERAPEUTICS 

Morphine,  not  readily  soluble  in  water;  morphine  hydrochloride, 
soluble  in  17.5  of  water  and  52  of  alcohol;  and  morphine 
sulphate,  soluble  in  15.5  of  water  and  565  of  alcohol.    One 
grain  of  morphine  sulphate  is  equivalent  to  about  f  grain 
of  pure  morphine.     Dose,  |  grain  (0.015  gm-)- 
Not  recognized  by  the  Pharmacopoeia  are: 
Compound  morphine  powder  (Tully  powder)  containing  1.5 
per  cent,  of  morphine  sulphate,  with  camphor,  licorice, 
and  chalk.    Dose,  10  grains  (0.7  gm.),  i.  e.,  about  ^  grain 
(0.009  gm.)  of  morphine  sulphate. 

Magendie's  solution,  which  is  composed  of  one  part  of 
morphine  sulphate  in  30  of  water,  i.  e.,  5  minims  =  | 
grain  of  morphine  sulphate.  It  slowly  weakens  and  ac- 
quires a  brown  color,  owing  to  the  formation  of  oxydi- 
morphine. 

Narcophin,  a  combination  of  33  per  cent,  of  morphine 
meconate  with  67  per  cent,  of  narcotine  meconate. 
Macht  says  that  the  narcotine  seems  to  activate  the 
morphine,  so  that  the  dose  is  that  of  morphine. 
Pantopon,  a  preparation  purporting  to  be  composed  of  the 
alkaloids  of  opium  in  the  same  proportion  as  in  opium 
itself,  but  in  4  times  the  strength.  Dose,  twice  that  of 
morphine. 

Pleistopon,  a  similar  preparation  with  the  narcotine  re- 
moved. 

Pharmacologic  Action. — The  work  of  Macht  on  combinations 
of  the  alkaloids  suggests  certain  advantages  in  the  use  of  opium 
or  mixtures  of  alkaloids  in  preference  to  morphine.  According 
to  Pal,  Macht,  Jackson,  and  others  the  alkaloids  of  the  phen- 
anthrene  group  (morphine,  codeine,  heroine,  dionine)  are  prone 
to  stimulate  the  smooth  muscles  of  the  hollow  viscera,  such  as  the 
bronchi,  bladder,  ureter,  gall-bladder,  intestines,  uterus,  and  the 
ducts  of  the  testes,  while  those  of  the  oxy-quinoline  group 
(papaverine,  narcotine)  relax  smooth  muscle.  But  Barbour 
obtained  no  effect  from  morphine  on  the  uterus,  and  it  scarcely 
seems  that  stimulation  of  smooth  muscle  can  be  a  clinical  effect 
of  morphine.  The  action  of  morphine  is  as  follows: 

Local. — Morphine  has  a  very  slight  local  action.  Its  control 
over  pain  is  essentially  central,  therefore  because  it  must  be 
absorbed  and  must  reach  the  centers  before  it  can  lessen  pain, 
morphine  or  opium  applied  to  a  painful  spot  has  no  more  power 
to  relieve  pain  at  that  spot  than  a  dose  given  by  mouth;  and, 
alter  local  application,  pain  is  relieved  in  distant  parts  of  the 
body  as  readily  as  at  the  site  of  application.  Hence  the  use  of 
morphine  or  opium  in  dusting-powder,  suppository,  or  ointment 


OPIUM  375 

is  irrational,  is  without  advantage,  and  has  the  disadvantage  of 
uncertainty  of  absorption. 

Stomach. — Through  its  central  action  it  tends  to  lessen 
motor  activity  and  to  retard  the  secretion  of  gastric  juice. 
Riegel,  also  Hirsch,  asserts  that  after  a  temporary  diminution  the 
secretion  increases  to  beyond  the  normal.  The  motor  functions 
are  decidedly  retarded.  Hirsch  noted  a  tonic  spasm  of  the  pyloric 
sphincter,  and  this  was  confirmed  by  the  #-ray  observations  of 
Magnus  on  cats.  Instead  of  two  or  three  hours  for  the  stomach 
to  empty  itself,  a  hypodermic  of  |  grain  (o.oi  gm.)  made  the 
emptying  time  eight  to  twelve  or  even  twenty-four  hours,  the 
fundal  end  of  the  stomach  tending  to  dilate  and  lose  its  tone. 
In  many  Roentgen-ray  examinations  in  12  patients,  Pancoast 
and  Hopkins  obtained  in  most  instances  some  pyloric  spasm  with 
prolongation  of  the  emptying  time,  the  effect  being  the  same 
whether  the  drug  was  given  by  mouth  or  subcutaneously. 
There  was  usually  hyperperistalsis  at  the  pyloric  end  of  the  stom- 
ach. Miiller  and  Saxl  noted  dilatation  of  the  fundus,  with  a 
doubling  of  the  capacity  of  the  stomach.  Rarely  an  hour- 
glass contraction  occurs.  Morphine  may  thus  be  a  cause  of 
acute  dilatation  of  the  stomach. 

Our  chief  concern  as  regards  the  stomach  is  the  undesirable 
after-effect  of  nausea  and  vomiting.  To  what  these  are  due  is 
not  positively  known.  A  dog  regularly  vomits  a  few  minutes 
after  a  dose  of  morphine — even  a  minute  dose,  as  o.oooi  gm.  per 
kilo — whether  given  by  mouth  or  hypodermatically;  but  in  man 
there  is  no  nausea  for  several  hours.  Hatcher  says  that  dogs 
do  not  vomit  if  the  morphine  is  preceded  by  atropine.  That 
the  effects  are  not  due,  at  least  in  man,  to  excretion  of  morphine 
itself  is  indicated  by  the  fact  that  doses  administered  by  mouth 
have  no  especially  nauseating  effect  before  absorption,  and  by 
Alt's  finding  that  after  a  hypodermic  injection  morphine  appeared 
in  the  saliva  in  two  and  one-half  minutes,  and  in  the  gastric 
secretion  in  three  minutes,  and  had  disappeared  from  the 
stomach  in  an  hour — long  before  the  nausea  developed.  It 
would  seem  to  be  due,  therefore,  in  man,  to  the  formation  from 
the  morphine  of  some  substance  with  an  apomorphine  effect 
upon  the  vomiting  center.  In  spite  of  this  nauseating  tendency, 
morphine,  because  of  its  central  sedative  action,  will  prevent  the 
production  of  vomiting  by  irritants  in  the  stomach. 

Intestines. — Morphine  diminishes  both  secretion  and  peristal- 
sis, but  particularly  the  latter;  and  so  powerful  is  it  that  it  is 
regularly  employed  in  peritonitis,  or  after  operations  where  it  is 
essential  to  keep  the  intestines  quiet.  Because  of  this  ability  to 
keep  the  bowel  immovable  it  is  sometimes  called  the  ''bowel 


376  PHARMACOLOGY   AND   THERAPEUTICS 

splint."  It  acts  when  the  intestine  is  severed  from  the  central 
nervous  system,  and  apparently  by  depressing  the  nerve  centers 
in  the  intestinal  walls  (Auerbach's  plexus).  After  morphine  even 
local  irritants  of  the  intestines  do  not  induce  peristalsis.  This 
morphine  constipation  is  often  very  undesirable  and  a  great  draw- 
back to  the  use  of  morphine.  A  factor  which  perhaps  contributes 
to  the  constipation  is  the  stomach  retention,  which  not  only 
causes  delay  in  the  passage  of  food,  but  permits  such  increased 
digestion  as  to  lessen  the  food  residue,  which  is  a  normal  intes- 
tinal stimulant.  Some  observers  report  a  tendency  to  accumula- 
tion in  the  lower  ileum  and  assume  that  this  is  caused  by  a 
closure  of  the  ileocolic  valve  similar  to  that  of  the  pylorus; 
but  Pancoast  and  Hopkins  find  decreased  motility  throughout 
the  small  intestine,  especially  in  the  upper  part  of  the  jejunum. 
All  investigators  agree  that  there  is  little  if  any  effect  on  the  colon. 

Large  doses  of  opium  occasionally  result  in  diarrhea,  and  this 
effect  may  be  due  to  muscle  stimulation  by  members  of  the  phen- 
anthrene  group.  Sometimes  in  painful  chronic  disease  requiring 
much  morphine  a  long-standing  constipation  will  suddenly  change 
to  an  intractable  diarrhea,  and  this  may  be  a  terminal  condition, 
death  following  in  three  or  four  days.  In  some  cases,  too,  where 
constipation  results  from  colicky  spasms,  a  dose  of  morphine,  by 
allaying  irritation  and  allowing  peristalsis  to  go  on,  may  cause 
the  bowels  to  move.  In  colic  or  pain  due  to  an  irremovable 
source  of  irritation,  e.  g.,  adhesions,  morphine  may  be  required 
to  allay  the  pain;  but  it  should  never  be  employed  until  all  doubt 
as  to  the  immediate  necessity  of  surgical  interference  is  settled. 
Many  deaths  have  resulted  owing  to  the  postponement  of 
operation,  because  of  the  masking  of  the  symptoms  by  morphine. 

Absorption. — Morphine  is  absorbed  very  rapidly  through  mu- 
cous membranes,  and  slowly,  if  at  all,  through  the  unbroken  skin. 
When  opium  is  used,  the  extractive  matters  retard  the  absorption 
of  the  alkaloids. 

Circulation. — The  direct  effect  upon  heart  and  arteries  is  prac- 
tically none.  Sollmann  says  there  is  slight  stimulation  of  cardiac 
muscle,  and  Macht  reports  slight  dilatation  of  the  coronary 
arteries.  But  there  is  stimulation  of  the  vasoconstrictor  center 
and  an  important  stimulation  of  the  vagus  center,  the  heart,  after 
a  large  dose,  being  slowed  even  to  the  extent  of  10  or  20  beats 
per  minute  without  change  in  arterial  pressure.  An  element  in 
the  slowing  may  also  be  the  quiet  induced.  Hering  reports 
heart-block  and  auricular  fibrillation;  the  author  has  seen  2 
cases  of  heart-block.  In  addition,  the  cutaneous  arterioles  may 
be  dilated,  with  flushing  of  the  skin.  In  poisoning  by  morphine 
the  heart  frequently  remains  strong  until  near  death,  so  that  more 


OPIUM  377 

vigorous  restorative  measures  may  be  adopted  than  in  poisoning 
by  other  narcotics. 

Respiration. — In  the  use  of  morphine  in  severe  diseases  the 
depression  of  the  respiration  is  a  serious  drawback.  A  resting 
rabbit,  expiring  200  c.c.  of  air  in  thirty  seconds,  was  given  \ 
grain  (o.oi  gm.)  of  morphine  (a  heavy  dose),  and  the  air  expired 
fell  to  90  c.c.  in  the  same  time.  Though  the  individual  respira- 
tions were  deeper,  the  breathing  was  greatly  slowed.  In  poisoning 
in  man  the  respiration  becomes  very  slow — even  down  to  three 
or  four  per  minute — the  individual  inspirations  being  deep  at 
first  but  eventually  shallow.  The  breathing  is  not  infrequently 
of  the  Cheyne-Stokes  type.  Macht  says  that  there  may  be  an 
unmistakable  effect  on  breathing  from  less  than  narcotic  doses. 
Cushny  and  Lieb  find  that  the  action  is  on  the  intrinsic  rhythm 


Fig.  45. — Record  showing  typical  Cheyne-Stokes  respiration  (from  a  case  of 
aortic  and  mitral  insufficiency  with  arteriosclerosis).  The  time  record  gives 
seconds  (Howell). 

of  the  respiratory  center,  and  that  the  rate  of  respiration  is 
decreased  independently  of  the  depth. 

Relation  to  Carbon  Dioxide. — In  normal  sleep,  or  in  the  sleep 
following  the  ordinary  hypnotic  close  of  chloral  or  sulfonal,  the 
breathing  is  slowed  because  of  the  lessened  need  of  the  inactive 
body  for  oxygen,  but  there  is  no  change  in  the  percentage  of  car- 
bon dioxide  in  the  blood.  But  in  morphine  narcosis  the  breath- 
ing is  reduced  below  the  requirements  of  the  body,  and  the  blood 
slowly  accumulates  a  percentage  of  CO2  above  the  normal. 

Experiments  show  that  when  the  respiratory  center  loses  its 
sensitiveness,  a  greater  than  normal  percentage  of  COa  in  the 
blood  is  required  to  bring  about  respiration;  and  that  slow 
breathing,  or  even  Cheyne-Stokes  breathing,  may  be  the  result 
of  a  diminished  sensitiveness  of  the  respiratory  center.  Cheyne- 
Stokes  respiration  consists  of  alternating  periods  of  apnea  and 


378  PHARMACOLOGY   AND   THERAPEUTICS 

hyperpnea,  and  indicates  depression  of  the  respiration.  In  it 
there  must  be  a  larger  than  normal  percentage  of  CO2  in  the 
blood  or  the  center  is  not  stimulated  to  activity.  During  the 
pauses  of  apnea  the  CO2  accumulates,  and  during  the  active 
breathing  CO2  is  given  off  until  a  state  of  acapnia  and  overoxy- 
genation  results.  However,  the  amount  of  oxygen  available 
makes  no  difference,  for  it  is  not  a  question  of  the  amount  of 
oxygen  in  the  blood,  but  of  the  amount  of  CO2.  Indeed,  the 
depression  of  respiration  may  be  in  large  measure  overcome  by  the 
inhalation  of  CO2  (Leonard  Hill). 

In  this  we  find  an  explanation  of  the  depression  of  respiration 
and  the  Cheyne-Stokes  breathing  of  morphine;  viz.,  a  lessened 
sensitiveness  of  the  respiratory  center  to  stimulation  by  CO2.  The 
center  is  still  subject  to  reflex  stimulation,  for  a  sudden  arousing 
of  the  patient  is  accompanied  by  improved  breathing  for  a  time, 
and  a  dash  of  cold  water,  even  in  coma,  may  induce  several  deep 
respirations.  Macht  has  shown  that  the  combination  of  mor- 
phine with  narcotine  or  papaverine  is  much  less  depressing  to  the 
respiration  than  morphine  alone. 

Cough  is  also  overcome,  the  central  depression  lessening  the 
reflex  from  mucus  or  from  an  area  of  irritation  in  the  respiratory 
tract.  This  effect  on  cough  is  a  highly  valuable  one  in  therapeu- 
tics, but  it  is  undesirable  or  even  dangerous  when  there  is  an  ex- 
cessive production  of  mucus  or  exudate,  which  should  be  coughed 
out. 

The  bronchial  secretions  are  somewhat  decreased,  but  this  is 
not  an  important  property  in  therapeutics. 

Nervous  System. — A  therapeutic  dose  of  morphine  lengthens 
the  reaction  time  to  stimuli,  lessens  the  sensitiveness  to  pain  and 
other  disturbing  factors,  and  promotes  a  dreamy,  abstracted  state 
of  the  mind;  or  it  induces  sleep.  These  effects  occur  without  any 
essential  muscular  relaxation  or  circulatory  depression.  That 
the  senses  are  less  keen  has  been  shown  in  the  case  of  touch  by 
the  esthesiometer,  in  the  case  of  sight  by  special  apparatus,  in 
the  case  of  pain  by  vast  clinical  experience.  That  mental  activity 
is  lessened  is  demonstrated  by  the  increased  time  required  to 
add  a  column  of  figures  or  to  answer  questions;  but  there  is  never 
such  depression  of  the  intellect  as  from  alcohol.  Morphine  acts 
chiefly  by  dulling  the  perceptions.  It  is  noteworthy  that  slight 
stimuli,  such  as  ordinary  pinching  or  noises,  or  steady  contin- 
uous stimuli,  like  continuous  pain  (unless  very  severe),  are  un- 
appreciated after  a  moderate  dose  of  morphine  and  do  not  prevent 
sleep;  yet  a  sudden  strong  stimulus,  such  as  a  flash  of  lightning  or 
the  deep  prick  of  a  pin,  may  arouse  one  almost  as  promptly  as 
usual,  unless  a  large  dose  has  been  taken. 


OPIUM  379 

Morphine  has  the  power,  above  all  other  drugs,  to  overcome 
pain  and  to  compel  sleep,  in  spite  of  everything  which  ordinarily 
tends  to  keep  the  patient  awake.  But  in  the  presence  of  very 
severe  pain  sleep  from  large  doses  may  not  be  any  deeper  or 
more  prolonged  than,  without  pain,  it  would  be  from  a  much 
smaller  dose.  Unfortunately,  morphine  has  undesirable  side- 
effects,  and  in  some  chronic  cases  with  severe  pain  these  prevent 
the  administration  of  sufficient  quantities  to  give  ease  to  the 
patient. 

Morphine  stands  by  itself  in  its  power  to  allay  pain,  to  lessen 
anxiety  and  nervous  fear,  and  to  change  discomfort  into  comfort. 
In  chronic  incurable  diseases  it  may,  even  in  doses  as  small  as 
sVrV  grain  (0.003-0.005  gm.),  dull  the  perceptions,  promote 
ease  of  mind,  and  prevent  worry  and  physical  distress. 

Ordinarily  after  a  dose  of  morphine  there  is  no  appreciable 
period  of  exhilaration;  but  in  the  habitue,  as  the  dreamy  condi- 
tion comes  on,  the  emotional,  imaginative,  and  animal  tendencies 
are  set  free  to  some  extent  before  sleep  supervenes.  This  suggests 
the  alcohol  effect,  but  the  narcosis  of  morphine  differs  from  that 
of  alcohol  in  that  there  is  not  the  great  depression  of  the  intellec- 
tual and  motor  powers.  For  when  a  morphine  patient  is  aroused 
he  can  reply  to  questions  rationally,  i.  e.,  with  the  intelligence 
that  any  one  might  show  on  being  aroused  from  a  deep  sleep, 
and  he  can  speak  clearly  and  can  use  his  limbs,  though  he  relapses 
promptly  into  sleep  on  being  left  alone.  There  is  no  effect  from 
morphine  that  corresponds  with  the  stupidity  and  muscular  re- 
laxation of  a  drunken  man.  A  morphine  patient  always  brightens 
up  on  being  aroused,  and  his  breathing  improves,  so  that  from  a 
person  who  looks  dangerously  depressed  and  "doped,"  he  changes 
to  one  that  can  smile  and  reply  to  questions.  If  allowed,  he 
promptly  relapses  into  sleep,  but  the  sleep  is  at  first  light,  and  it 
is  some  time  before  he  again  reaches  the  stage  of  deep  depression. 
In  cats  and  some  human  beings,  mostly  women,  cerebral  stimula- 
tion and  excitement  regularly  result  instead  of  depression. 

Motor  Areas. — The  motor  area  of  the  cortex  is  not  found  to 
have  lost  its  excitability  to  any  great  extent,  as  after  chloral  or 
bromide,  so  that  a  dog  will  die  from  respiratory  depression  before 
there  is  lessened  response  to  electric  stimulation  (Hitzig  and 
others) .  But  voluntary  muscular  activity  is  sluggish  because  of 
the  diminished  perception  of  stimuli  and  the  sluggishness  of  cere- 
bral activity.  There  may  be  some  incoordination,  and  this  is 
attributed  to  depression  of  the  cerebellum. 

Spinal  Cord. — In  some  of  the  lower  mammals,  c.  g.,  the  cat, 
there  is  increased  activity  of  the  reflexes,  and  there  may  be  con- 
vulsions of  the  typical  strychnine  type.  In  man,  however,  there 


380  PHARMACOLOGY   AND   THERAPEUTICS 

is  probably  moderate  depression  of  the  reflexes,  but  the  cord  re- 
flexes are  not  so  much  depressed  as  by  chloral  or  bromides,  and 
the  tone  of  muscle  is  not  lost,  i.  c.,  there  is  no  essential  muscular 
relaxation.  Hence  morphine  is  not  good  in  strychnine  poisoning. 
Occasionally  in  fatal  poisoning  in  man  the  patient  has  manifested 
convulsions  of  the  strychnine  type.  McGuigan  and  Rose 
attribute  this  to  an  oxidation  product  formed  in  the  body,  but 
undoubtedly  asphyxia  plays  a  part  in  its  production.  The 
author  has  seen  typical  asphyxial  convulsions  in  a  case  of  loco- 
motor  ataxia  a  few  minutes  after  a  hypodermic  of  |  grain  (0.03 
gm.). 

Medulla. — By  good-sized  therapeutic  doses  the  vagus,  vaso- 
constrictor, and  pupil-contracting  centers  are  stimulated,  while 
the  respiratory,  the  cough,  the  temperature-regulating,  and  the 
secretory  centers  lose  their  sensitiveness. 

Peripheral  Nerves. — There  is  a  slight  local  analgesia  (Macht), 
but  skin  sensitiveness  is  diminished  because  of  diminished  per- 
ception of  stimuli. 

The  Eye. — After  good-sized  therapeutic  doses,  or  sometimes 
after  the  habitual  dose  of  a  morphine  devotee,  the  pupils  become 
contracted.  In  marked  poisoning  the  contraction  is  extreme  and 
makes  the  so-called  "pin-point"  pupils  which  are  characteristic 
of  opium  poisoning.  After  a  lethal  dose  the  pupil,  owing  to 
asphyxia,  very  widely  dilates  a  short  time  before  death,  so  that 
after  death  from  morphine  poisoning  the  pupils  are  found  to  be 
dilated.  In  animals  like  the  cat,  in  which  there  is  stimulation  of 
the  cerebrum,  morphine  dilates  the  pupil  from  the  beginning. 

Morphine  solution  dropped  in  the  eye,  or  injected  into  an 
enucleated  eyeball  (as  of  an  ox),  has  no  effect  upon  the  pupil,  so 
its  action  is  not  local  or  peripheral.  It  also  does  not  affect  the  eye 
through  the  third  nerve  ganglia  or  the  cervical  ganglia,  therefore 
its  action  must  be  purely  central.  That  it  stimulates  the  pupil- 
contracting  center  rather  than  depresses  the  pupil-dilating  center 
is  evident,  because  paralysis  of  the  latter  will  not  result  in  pin- 
point pupils,  or  produce  the  wide  dilatation  of  the  late  stage  of 
poisoning.  This  late  dilatation  is  probably  entirely  the  result  of 
asphyxia. 

The  Secretions. — From  depression  of  the  secretory  center 
almost  all  the  secretions  are  diminished,  but  this  is  a  minor  effect 
in  therapeutics.  The  sweat  is  increased,  but  not  markedly  so, 
unless  the  drug  is  given  with  a  copious  hot  drink.  In  health  the 
urine  is  not  essentially  changed;  but  in  nephritis  it  is  believed  by 
Tyson  and  others  to  be  decreased.  A  satisfactory  explanation  of 
this  is  not  forthcoming. 

Metabolism. — The  quiet  and  the  depressed  respiration  result 


OPIUM  381 

in  lessened  tissue-waste  and  decreased  oxidation.  The  glycogen 
of  the  liver  may  disappear,  and  increased  lactic  acid  and  sugar 
appear  in  the  blood,  the  hyperglycemia  sometimes  resulting  in 
glycosuria. 

Temperature. — In  poisoning  the  fall  of  temperature  may  be 
as  much  as  2  degrees;  and  since  80  per  cent,  of  the  fall  is  due  to 
diminished  production  of  heat,  and  only  a  slight  amount  to  in- 
creased heat  dissipation,  the  drop  in  temperature  must  result 
from  the  bodily  quiet,  rather  than  from  the  dilatation  of  the 
cutaneous  vessels  and  sweating.  Morphine  is  not  employed  in 
therapeutics  as  an  antipyretic.  The  author  has  seen  fever  of 
102.6°  F.  with  a  skin  rash  and  sickness  of  three  or  four  days 
follow  a  single  dose  of  morphine,  the  patient  reporting  that  this 
was  his  second  experience  of  the  kind.  An  irregular  temperature 
has  been  reported  in  chronic  opium  takers. 

Excretion. — After  a  hypodermatic  injection,  the  drug  has  been 
found  in  the  mouth  in  two  and  a  half  minutes,  and  in  the  stomach 
in  three  minutes,  and  it  continues  to  be  found  in  the  stomach  all 
through  the  period  of  morphine  action  (Marme).  In  dogs,  about 
30  per  cent,  of  morphine  given  hypodermatically  can  be  recovered 
from  the  stomach,  a  fact  which  suggests  the  value  of  lavage  in 
poisoning.  About  30  or  40  per  cent,  more  may  be  recovered  in  the 
feces  (Faube,  Faust).  It  is  evident,  therefore,  that  a  certain 
amount  of  reabsorption  and  reexcretion  must  go  on  in  the  alimen- 
tary tract,  with  the  final  result  of  either  destruction  of  the  mor- 
phine or  its  discharge  with  the  feces.  Traces  of  morphine  also 
appear  in  the  milk,  sweat,  and  urine,  and  the  remainder  is  oxidized 
to  the  comparatively  inactive  oxydimorphine,  some  of  which  is 
excreted  in  the  urine.  Heffter  claims  that  one-third  is  eliminated 
by  the  kidneys,  but  most  authors  report  only  traces.  Cloetta 
was  unable  to  obtain  tests  of  morphine  in  the  blood  after  twenty 
minutes,  and  determined  that  it  had  totally  disappeared  from  the 
body  in  two  days. 

Rarely  some  morphine-glycuronic  acid  appears  in  the  urine 
and  may  react  with  Fehling's  solution.  Rarely  also  there  is  a 
true  glycosuria.  The  odorous  substances  of  opium  are  excreted 
mostly  in  the  urine. 

Though  it  is  found  in  the  fetal  blood,  it  does  not  seem  to 
affect  the  fetus,  probably  because  the  latter  does  not  maintain  its 
vitality  by  its  respiratory  apparatus.  The  newborn  babe  of  a 
habitue  may,  however,  fail  to  breathe,  or  if  it  lives  may  require 
its  habitual  dose  if  the  amount  excreted  in  the  mother's  milk 
is  insufficient,  or  if  the  child  is  taken  from  the  breast.  If  a 
large  dose  of  morphine  is  given  to  a  non-habituated  mother  just 
before  delivery,  it  may  disastrously  affect  the  infant's  breathing. 


382  PHARMACOLOGY   AND   THERAPEUTICS 

The  Bladder. — In  poisoning  there  may  be  failure  of  the  re- 
flexes, and  spasm  of  the  sphincter  with  retention  of  urine. 

Kidneys. — Ordinarily  there  is  no  effect,  but  in  uremia  the  drug 
seems  to  increase  the  inefficiency  of  the  kidneys  (Tyson). 

After-effects. — Not  uncommon  after  a  medicinal  dose  are: 
nausea,  vomiting  and  constipation,  with  perhaps  headache,  dizzi- 
ness, and  general  lassitude.  For  a  short  time  after  a  hypoder- 
mic dose  there  may  be  a  very  slow  "vagus"  pulse. 

Untoward  Effects. — Excitement  instead  of  quiet,  an  effect 
seen  mostly  in  women,  and  common  among  eastern  women;  it 
is  the  regular  effect  in  cats.  Occasionally  there  is  diarrhea.  The 
author  has  observed  the  following  striking  untoward  effects,  viz. : 
(i)  Suspension  of  breathing  and  asphyxial  convulsions  from  -j 
grain  (0.03  gm.)  in  locomotor  ataxia.  (2)  Partial  heart-block 
f rom  a  hypodermatic  of  |  grain  (0.008  gm.).  (3)  Death  from  a 
change  of  partial  heart-block  to  complete.  On  several  occasions 
even  small  doses  had  caused  an  increase  in  the  block,  with 
Cheyne-Stokes  respiration.  The  fatal  dose,  ^  grain  (o.oi  gm.), 
was  given  by  a  newcomer  for  terrific  pain.  (4)  A  mottled  rash 
with  fever  of  102.6°  F.,  and  pains  in  the  joints.  (5)  Edema  of 
the  lungs  in  a  case  of  myocarditis  and  in  several  cases  of 
pneumonia.  Hering  reports  cases  of  heart-block  and  auricular 
fibrillation.  Arkin  states  that  morphine  tends  to  inhibit 
phagocytosis  in  streptococcus  infections. 

Susceptibility. — Very  young  and  very  old  people  are  especially 
susceptible  to  morphine,  and  in  such  the  drug  must  be  used  with 
special  caution.  The  dose  should  be  below  that  called  for  by  the 
ordinary  rules  for  dosage.  The  too  ready  use  of  paregoric  for 
infants  cannot  be  too  strongly  condemned,  for  many  deaths  have 
occurred  from  its  employment,  and  in  numerous  instances  an 
opium  habit  has  been  formed. 

Tolerance  is  fairly  easily  set  up,  and  not  only  is  there  an  in- 
creased power  of  the  body  cells  to  oxidize  the  morphine,  but  also 
an  increased  resistance  of  the  cells,  so  that  they  are  affected  less 
strongly  by  the  same  amounts  of  morphine.  Mclver  and  Price 
believe  that  an  antitoxic  substance  is  developed.  Faust  found 
in  dogs  that  the  ability  of  the  tissues  to  destroy  morphine  was 
increased,  so  that  as  tolerance  was  established  none  of  the  mor- 
phine was  excreted.  Riibsamen,  experimenting  with  rats,  and 
Cloetta  with  dogs,  in  which  tolerance  had  been  established, 
isolated  large  quantities  of  unchanged  morphine  from  the  tissues. 
Van  Dongen  (1915)  found  that  he  could  increase  the  tolerance  of 
the  respiratory  center  even  to  1800  times  the  normal  dose. 
Wholey  reports  cases  taking  25  grains  (1.7  gm.)  and  60  grains 
(4  gm.)  as  the  daily  dosage.  We  have  encountered  a  case  that 


OPIUM  383 

was  reported  to  be  receiving  96  grains  (6.4  gm.)  a  day.  Dr. 
Alex.  Lambert  has  told  me  of  a  case  taking  45  grains  (3  gm.) 
at  one  dose.  Leu  reports  the  consumption  by  a  man  of  34,800 
grains  (2255  gm.)  of  morphine  in  about  two  years.  In  dogs 
having  an  acquired  tolerance  for  morphine,  there  is  an  altered 
susceptibility  to  related  narcotics,  diarrhea,  for  example,  result- 
ing from  codeine  or  heroine  (Myers). 

Toxicology. — Acute  poisoning  is  not  uncommon,  among  both 
children  and  adults.  Death  has  been  reported  from  about  3 
grains  of  morphine  sulphate.  A  single  large  dose  has  occasionally 
resulted  in  prompt  vomiting  and  the  expulsion  of  the  drug,  but 
this  is  unusual.  Practically,  the  poisoning  shows  three  stages  or 
degrees. 

Poisoning  in  the  first  degree  is  not  infrequently  seen  from  the 
physician's  administration  of  the  drug  to  relieve  pain.  There  are : 
Rather  slow  respiration,  slow  heart  but  good  blood-pressure,  and 
contracted,  though  not  pin-point,  pupils.  The  patient  is  sluggish 
and  inattentive,  may  or  may  not  be  sleeping,  and,  on  being 
spoken  to  or  asked  to  do  something,  may  rouse  up  for  a  time  and 
look  better  and  brighter;  but  he  soon  relapses  into  the  previous 
state  of  lethargy  and  inattention,  or  sleep  There  may  be  nausea, 
perhaps  retching  or  vomiting.  The  treatment  is  strong  coffee  by 
mouth  or  rectum,  or  hypodermatics  of  caffeine,  and  plenty  of  air. 
Atropine  and  strychnine  may  also  be  of  value.  Lavage  of  the 
stomach  is  sometimes  useful  to  lessen  nausea  and  remove  some  of 
the  drug. 

The  second  degree  of  poisoning  results  in  stupor,  a  stage  which 
supervenes  in  from  fifteen  to  thirty  minutes.  The  face  is  cyanotic, 
flushed,  the  skin  warm,  the  respirations  regular,  and  only  4  to  10 
per  minute,  or  Cheyne-Stokes  in  character,  the  heart  slow,  though 
blood-pressure  remains  good,  the  pupils  pin-point,  and  the  patient 
in  a  state  of  unconsciousness  from  which  he  can  be  aroused  only 
with  great  difficulty.  When  aroused,  he  brightens  up,  has  in- 
telligence, can  talk  distinctly,  and  can  be  made  to  walkabout 
(difference  from  alcoholism);  but  if  allowed,  he  relapses  at  once 
into  sleep,  which  soon  again  becomes  a  deep  stupor.  There  may 
be  retention  of  urine. 

Treatment. — (i)  Potassium  permanganate,  i  to  2  grains  (0.06- 
0.12  gm.)  in  solution  at  intervals  by  mouth  to  oxidize  any  mor- 
phine that  may  be  in  the  stomach,  that  excreted  as  well  as  that 
which  has  not  been  absorbed.  (2)  Lavage  of  the  stomach  at 
intervals  with  water  or  i  :  2000  potassium  permanganate  solution. 
(3)  Colon  irrigation  to  remove  the  morphine  as  it  is  excreted,  and 
so  prevent  its  reabsorption.  (4)  The  hourly  administration  of 
maximal  doses  of  caffeine,  atropine,  or  black  coffee  until  the  de- 


384  PHARMACOLOGY   AND   THERAPEUTICS 

pression  of  respiration  is  overcome.  (5)  Ceaseless  activity — 
above  all  things  keep  patient  awake  and  active,  for  in  this  stage  if 
he  relapses  into  sleep  the  patient  rapidly  and  seriously  loses 
ground.  As  the  heart  usually  continues  strong  and  there  is  no 
muscular  weakness,  vigorous  measures  may  be  employed  to  keep 
him  active,  e.  g.,  he  may  be  walked  about,  and  if  necessary  lashed 
with  a  wet  towel  or  whip.  (6)  Catheterization,  if  required. 

The  third  degree  of  poisoning  is  manifested  by  coma  and  col- 
lapse. The  patient  cannot  be  aroused,  the  skin  is  cyanotic,  cold, 
and  clammy,  the  pulse  is  weak,  the  respirations  are  very  infre- 
quent and  shallow — either  regular,  at  the  rate  of  three  or  four  a 
minute,  or  Cheyne-Stokes  in  type.  Rarely,  there  are  strychnine- 
like  convulsions  or  the  convulsions  of  asphyxia.  Death  takes 
place  from  paralysis  of  the  respiratory  center.  Shortly  before 
death  the  pupil  may  widely  dilate.  The  treatment  is  that  for 
severe  collapse,  with  absolute  repose,  artificial  respiration,  oxy- 
gen, carbon  dioxide,  and  the  administration  of  caffeine.  The 
prognosis  after  the  patient  passes  into  this  coma  stage  is  exceed- 
ingly unfavorable. 

Morphine  Habit. — Chronic  Poisoning  or  Morphinism.— 
Opium,  and  its  alkaloid  morphine,  are  vicious  habit-drugs,  the 
habit  being  common  among  physicians,  nurses,  and  druggists. 
The  drug  may  be  taken  by  hypodermatic  injection,  by  mouth,  or 
by  the  inhalation  of  opium  fumes  (opium  smoking).  The  last 
method  is  said  to  be  the  least  pernicious.  When  the  devotee  does 
not  get  his  usual  dose  he  is  nervous,  restless,  irritable,  and  unable 
to  concentrate  his  mind  upon  his  work;  when  he  gets  his  drug  he  ex- 
periences a  return  of  his  energy,  feels  comfortable,  and  is  in  better 
spirits.  He  soon  then  passes  into  a  dreamy,  imaginative  state  of 
mental  and  bodily  satisfaction,  i.  e.,  wholly  indifferent  to  outside 
influences,  and  forgets  his  responsibilities  and  his  troubles;  then 
comes  sleep,  usually  of  a  stuporous  kind,  and  on  awaking  there 
may  be  nausea,  headache,  languor,  and  nervousness. 

The  prolonged  use  frequently  results  in  digestive,  nervous, 
and  mental  troubles,  viz.,  loss  of  appetite,  nausea,  and  obstinate 
constipation;  irritability  of  temper,  loss  of  will-power  and  self- 
control,  mental  depression,  and  if  the  habit  is  a  bad  one,  a  ten- 
dency to  moral  depravity  (develop  low,  vulgar  tastes,  are  fright- 
ful liars,  etc.) ;  irregular  heart  tremors,  anemia  and  wasting,  some- 
times an  irregular  temperature,  polyuria,  and  perhaps  albumin- 
uria  or  glycosuria,  and  often  sexual  impotence  and  amenor- 
rhea.  The  writer  delivered  a  devotee  of  fourteen  years'  stand- 
ing whose  husband  had  been  a  habitue  for  over  twenty  years. 
The  child  was  not  well-nourished,  but  thrived  on  the  breast. 
During  her  stay  in  the  hospital  the  mother  received  her  daily 


OPIUM  385 

dosage.  From  an  experience  with  12,000  cases  at  the  Tombs, 
New  York,  McGuire  and  Lichtenstein  report  a  wonderful  growth 
of  hair  in  women  habitues. 

Treatment. — i.  Isolation  from  friends  and  hirelings. 

2.  Gradual  withdrawal  of  the  drug  in  from  two  or  three 
days  to  a  week.     Accompanying  the  withdrawal  there  may  be 
diarrhea,  cramps  in  abdomen,  back,  and  legs,  intense  restlessness, 
mental  and  physical  suffering,  and  collapse.    Valenti  has  shown 
that  the  withdrawal  symptoms  in  dogs  are  arterial  hypotension 
and    arhythmia,   and    that   the    serum    after   withdrawal   will 
produce  the  same  condition  in  normal  dogs.    Talmey  attributes 
some  of  the  withdrawal  symptoms  to  acidosis,  and  reports  a  case 
developing  coma  from  this  cause.     Stokes  finds  a  sympathico- 
tonic  state. 

3.  The  substitution  for  a  time  of  other  drugs,  of  which  great 
favorites  are  atropine,  hyoscine,  dionine,  and  codeine.     Keeping 
the  patient  in  a  state  of  partial  narcosis  for  several  days  tends  to 
prevent  the  discomforts  which  cause  the  craving  for  morphine. 

4.  Nourishing  food,  to  the  extent  of  overfeeding. 

5.  Massage,  baths,  and  general  measures  to  improve  the  hy- 
gienic conditions  of  living. 

6.  Excessive  and  persistent  purgation. 

7.  Removal  of  the  original  cause  of  the  habit,  as  by  operation 
on  an  ovary  or  other  source  of  pain. 

In  morphinism  there  is  no  hereditary  neuropathic  tendenc)^  as 
there  is  in  alcoholism,  and  the  cause  of  the  continuance  of  the 
morphine  habit  is  the  distress  of  the  withdrawal  symptoms.  The 
morphinist  will  often  desire  to  give  up  the  drug,  but  never  does 
so  of  his  own  free  will,  because  he  cannot  stand  the  physical  suf- 
fering. Yet  morphine  patients  have  a  greater  desire  to  reform 
than  alcoholics  have,  and,  when  once  reformed,  are  quite  likely 
to  remain  so,  unless  the  pain  or  worry,  etc.,  which  was  the  original 
cause  of  the  habit,  recurs.  Often  they  go  back  to  the  drug  for 
relief  from  suffering,  rather  than  because  of  any  special  crav- 
ing for  it.  Stomach  symptoms  must  be  especially  guarded 
against,  as  they  are  always  attributed  to  abstinence  from  the 
drug. 

Without  some  systematic  method  of  treatment  it  is  one  of  the 
most  difficult  tasks  to  check  a  morphine  habit,  and  the  habitue 
will  take  paregoric,  and  even  Sun  Cholera  Drops,  for  the  morphine 
they  contain. 

The  cutting  off  of  the  habitual  dose  because  of  some  intercur- 
rent  illness,  such  as  pneumonia,  causes  needless  suffering  and 
danger.     Collapse  for  want  of  the  drug  has  been  reported  in  in- 
fants born  of  habitues. 
25 


386  PHARMACOLOGY   AND   THERAPEUTICS 

The  Lambert  method,  employed  at  Bellevue  Hospital,  consists 
of  the  administration  of  a  specific  remedy,  of  decreasing  doses  of 
the  opiate,  and  of  powerful  cathartics.  It  is  as  follows: 

1.  The  specific  consists  of  a  mixture  of  15  per  cent,  tincture 
of  belladonna,  2  parts,  with  i  part  each  of  the  fluidextracts  of 
xanthoxylum  and  hyoscyamus.     It  is  administered  every  hour, 
beginning  with  6  drops  and  increasing  2  drops  per  dose  every  six 
hours.     It  is  continued  until  belladonna  symptoms  are  noticed 
or  there  is  a  thick,  green  stool. 

2.  The  opiate — after  the  first  free  catharsis  give  two- thirds 
the  total  habitual  daily  dose  of  morphine  or  opium  in  3  divided 
doses  at  half-hour  intervals.     After  the  action  of  the  second  dose 
of  the  cathartic  (about  the  eighteenth  hour)  give  one-third  the 
habitual  daily  dose.     About  the  thirty-sixth  hour,  give  one-sixth 
the  habitual  daily  amount.     If  very  nervous,  give  5  grains  (0.3 
gm.)  of  codeine  phosphate  hypodermatically. 

3.  The  cathartic — at  the  outset  give  5  compound  cathartic 
pills  and  5  grains  (0.3  gm.)  of  blue  mass,  followed  in  six  hours  by 
a  saline.     At  the  tenth  hour  after  the  first  dose  of  opiate  repeat 
the  pills  and  blue  mass,  and  six  hours  later  the  saline.     Ten 
hours  later  repeat  again,  followed  by  the  saline  if  necessary.  When 
a  thick,  bilious,  green  stool  appears,  give  2  ounces  of  castor  oil  to 
clean  out  the  intestines.     If  the  patient  is  weak,  give  strychnine 
or  digitalis. 

The  Stokes  method  is  based  on  the  idea  that  there  is  a  sym- 
pathicotonic  state  induced  by  the  withdrawal.  He  gives  enough 
morphine  to  prevent  withdrawal  symptoms,  and  injects  a  mixture 
of  pilocarpine  and  physostigmine  salts  every  two  or  three  hours. 
Petty 's  method  includes  large  doses  of  strychnine.  It  would  seem 
that  to  obtain  a  cure  as  much  depends  upon  the  physician  in 
charge  as  upon  any  method. 

The  morphine  habitue  is  prone  to  be  an  abominable  liar,  and 
five  minutes  after  taking  the  dose  will  state  emphatically  that 
he  has  not  taken  the  drug  for  weeks.  Tablet  triturates  found  in 
the  possession  of  a  suspect  may  be  tested  as  follows :  Dissolve  one 
in  0.5  c.c.  (8  minims)  of  water,  and  add  2  drops  of  the  tincture 
of  ferric  chloride:  a  blue  or  bluish-green  color  indicates  morphine. 
Sometimes  needle  punctures  in  the  arms  or  legs  will  confirm  the 
diagnosis,  or  a  state  of  dopiness  with  contracted  pupils,  or  a  test 
with  a  dose  of  morphine  to  see  if  it  gives  great  satisfaction.  A 
peculiar  blue  coloration  of  the  skin  in  the  region  of  the  needle 
punctures  has  been  described  as  "pigment  atrophy."  The 
author  has  seen  some  striking  cases. 

Therapeutics. — Morphine  or  opium  is  used  extensively  to 
allay  severe  pain,  and  to  overcome  restlessness  and  nervousness 


OPIUM  387 

or  anxiety  associated  with  sickness;  in  other  words,  to  promote 
ease  of  mind  or  body.     Some  of  its  more  special  uses  are: 

1.  To  check  vomiting. 

2.  To  stop  intestinal  peristalsis,  as  after  rectal  or  abdominal 
operations,  and  in  peritonitis;  and  to  check  excessive  peristalsis, 
as  in  intractable  diarrhea,  e.  g.,  that  of  tuberculosis.     Paregoric, 
or  the  pills  of  lead  acetate  and  opium,  each  i  grain  (0.06  gm.), 
or    of   camphor   and   opiuir,   are    preferred,   but   hypodermics 
of  morphine  are  also  effective.     In  the  presence  of  acute  ab- 
dominal pain  one  should  avoid  opiates  if  possible  until  the  diag- 
nosis is  determined. 

3.  To  quiet  a  nervous  heart,  or  rest  a  diseased  heart,  by  pro- 
moting general  rest  and  quiet. 

4.  To  lessen  pain. 

5.  To  relieve  the  pain  and  gastric  upset  in  migrainal  vomiting 
attacks. 

6.  To  relieve  the  pain  and  anxiety  of  angina  pectoris. 

7.  To  check  cough.     It  should  be  avoided  in  chronic  cough 
because  of  habit  formation. 

8.  To  lessen  worry  and  restlessness  in  acute  conditions,  such  as 
hemoptysis,  or  in  incurable  diseases,  such  as  cancer. 

9.  To  compel  quiet  and  sleep,  as  in  delirium  or  mania,  or  in 
spite  of  powerful  factors  which  tend  to  keep  the  patient  awake, 
such  as  pain. 

10.  As  a  preliminary  to  general  anesthesia,  to  quiet  the  mind 
and  promote  the  anesthesia.     It  is  frequently  given  with  hyoscine 
(scopolamine) .     Its  tendency  to  produce  nausea  and  vomiting, 
dilatation  of  the  stomach,  and  depression  of  the  respiration,  and 
its  interference  with  pupil  reactions  are  drawbacks  to  its  use. 

11.  To  induce  sweating  at  the  onset  of  a  cold,  in  the  form  of 
Dover's  or  Tully's  powder.     It  is  not  a  good  diaphoretic. 

12.  In  diabetes — opium,  morphine,  and  codeine  have  a  special 
power  to  bring  about  a  reduction  in  the  sugar  excretion;  and 
von  Noorden  attributes  this  to  the  quiet  of  the  body  and  the 
sleep  induced  by  their  use.     From  the  author's  experience  this 
explanation  of  the  action  seems  inadequate.     Klercker  was  able 
to  prevent  alimentary  hyperglycemia  following  large  amounts  of 
glucose,  an  effect  that  may  be  due  to  retardation  in  the  stomach 
and  consequent  retardation  of  absorption. 

13.  In   acute  paroxysmal  edema   of  the  lungs  it  is   specific 
(Stengel),  but  not  in  any  other  form  of  pulmonary  edema. 

Contraindications  or  Cautions. — It  should  not  be  used  in — (a) 
Conditions  with  much  depression  of  the  respiration,  as  in  edema 
of  lungs  (except  the  acute  paroxysmal  type),  Cheyne-Stokes 
breathing,  and  some  cases  of  pneumonia;  (b)  acute  dilatation 


388  PHARMACOLOGY   AND   THERAPEUTICS 

(paralysis)  of  stomach  or  bowels.  It  should  be  employed  cau- 
tiously in — (a)  nephritis,  especially  if  there  is  any  uremic  tend- 
ency; and  (b)  infancy  and  old  age.  The  work  of  Macht  would 
suggest  that  a  better  preparation  for  general  use  is  narcophin. 

Atropine  is  frequently  given  with  morphine  in  hypodermatic 
use.  It  tends  to  supplement  the  good  effect  on  pain  and  to  lessen 
the  nausea;  but  its  most  important  effects  are  to  counteract 
the  depression  of  respiration  and  perhaps  the  vagus  stimulation. 

Scopalamine-morphine  Anesthesia. — See  Belladonna  Group. 

CODEINE 

This,  the  methyl  ester  of  morphine,  is  a  weaker  narcotic,  and 
its  power  to  allay  pain  and  induce  sleep  is  very  much  less  than 
that  of  morphine.  Yet  where  the  lesser  effect  is  sufficient,  it  has 
the  following  advantages  over  morphine:  (i)  It  is  not  a  vicious 
habit-drug;  (2)  it  is  not  strongly  constipating,  and  (3)  it  is  less 
depressing  to  the  respiration.  Further,  codeine  differs  from 
morphine  in  that  it  is  excreted  largely  by  the  kidneys. 

In  Heinz's  experiments  with  rabbits  a  dose  of  i^  grains  (o.i 
gm.)  reduced  the  breathing  from  92  to  60  in  thirty-three  minutes, 
but  the  individual  inspirations  were  deeper,  so  that  at  the  eigh- 
tieth minute  the  air  inspired  had  increased  from  720  to  1000  c.c. 
per  minute.  With  morphine,  one-twentieth  this  amount  reduced 
the  rate  of  respiration  and  also  the  expired  air  to  nearly  one-half. 

In  allaying  cough  it  is  just  as  effective  as  morphine,  but  its 
dosage  must  be  fully  six  times  as  large.  A  matter  of  note  is  that 
with  a  very  slight  increase  beyond  the  hypnotic  dose,  a  stimulat- 
ing effect  upon  the  cord  may  appear,  with  restlessness  and  in- 
creased reflex  excitability  instead  of  quiet  and  sleep.  Its  chief 
uses  are  to  allay  mild  pain,  especially  abdominal  pain,  to  promote 
sleep  (usually  with  other  hypnotics,  such  as  trional  or  veronal), 
to  quiet  cough,  and  in  diabetes.  In  a  chronic  disease  like  the 
last  mentioned,  and  in  tuberculous  cough,  codeine  is  just  as  useful 
and  is  preferred  to  morphine  because  of  the  ease  with  which 
a  morphine-habit  is  established.  The  usual  dose  of  codeine  for 
cough  is  ,j  grain  (0.015  gm.),  and  for  pain,  \  grain  (0.03  gm.), 
repeated  every  three  or  four  hours;  for  hypodermatic  use  the 
phosphate  is  preferred  because  of  its  solubility.  The  author 
has  seen  two  codeine  habitues — they  were  broken  of  the  habit 
without  any  trouble. 

Apocodeine,  an  alkaloid  prepared  from  codeine,  has  a  different 
action.  It  is  employed  somewhat  in  the  laboratory  as  a  general 
paralyzant  of  sympathetic  nerve-endings.  In  this  respect  it 
directly  antagonizes  epinephrine.  In  therapeutics  it  has  been 
used  slightly  hypodermatically  in  dose  of  \  grain  (0.03  gm.) 


PAPAVERINE  389 

to  promote  intestinal  peristalsis.  It  acts  by  cutting  off  splanch- 
nic control  of  intestinal  activity  through  the  depression  of  the 
sympathetic  nerve-endings,  but  is  not  a  safe  drug  nor  a  very 
efficient  one  for  the  purpose. 

PAPAVERINE 

Papaverine,  as  the  hydrochloride,  soluble  in  alcohol  but  not 
readily  in  water,  or  the  sulphate,  soluble  in  both  water  and  alcohol, 
is  employed  locally  in  2  to  4  per  cent,  solution,  and  by  mouth  and 
subcutaneously  in  dose  of  ^  to  2  grains  (0.03-0.12  gm.).  Its 
solutions  are  unstable  and  must  be  kept  from  the  air  in  alkali- 
free  glass. 

Locally. — Applied  to  mucous  membranes  or  injected  beneath 
the  skin  there  is  slight  irritation,  followed  by  a  moderate  degree  of 
analgesia  and  a  relaxation  of  the  blood-vessels  and  tissues  of  the 
part. 

Central  Nervous  System. — There  is  a  depression  of  the  higher 
centers  like  that  of  morphine,  but  milder. 

Smooth  Muscle. — There  is  a  relaxation  of  smooth  muscle  in 
stomach,  intestines,  gall-bladder,  bile  passages,  ureter,  bladder, 
uterus,  and  the  arteries.  This  is  due  to  a  direct  effect  on  the 
muscle  and  not  through  any  action  on  the  nervous  elements. 
It  is  not  very  constipating. 

Heart. — Macht  found  that  small  doses  in  a  dog  caused  a  slight 
slowing  of  the  heart  and  a  marked  increase  in  tonicity  with  in- 
creased contractility  and  increased  volume  of  output.  As  there 
is  no  change  if  the  vagi  are  cut,  or  after  atropine,  or  if  the  accel- 
erator ganglia  are  destroyed,  the  action  is  a  direct  one  on  the 
cardiac  muscle.  Large  doses  in  the  frog  caused  heart-block  and 
death  with  the  heart  in  diastole. 

Arteries. — Owing  to  depression  of  muscle  it  is  a  powerful 
dilator  of  the  coronary  and  systemic  arteries  with  a  striking  fall 
in  arterial  pressure.  Pal  noted  very  little  effect  in  normal  animals 
or  in  those  with  chronic  high  blood-pressure,  but  a  striking  action 
after  epinephrine  or  pituitary. 

Respiration. — The  rate  is  slightly  decreased,  but  the  volume 
output  and  alveolar  ventilation  are  increased  and  there  is  a 
dilatation  of  the  bronchi.  After  an  intravenous  close  the  bron- 
chial muscles  were  relaxed  in  one  minute  (Pal). 

Elimination. — It  is  eliminated  by  liver,  kidneys  and  small 
intestine,  mostly  unchanged. 

Toxicity. — Bouchet  obtained  no  striking  effect  from  15  grains 
(i  gm.)  by  mouth.  In  the  frog  Macht  found  the  minimum  lethal 
dose  y-^nj  of  the  body  weight,  in  cats  55  mg.  per  kg.  had  no  effect, 
and  in  dogs  50  mg.  produced  a  notable  but  not  serious  narcosis. 


390  PHARMACOLOGY   AND   THERAPEUTICS 

Therapeutics. — It  is  used:  i,  to  overcome  smooth  muscle  spasm 
in  the  viscera,  as  cardiospasm,  pylorospasm,  intestinal  colic, 
biliary  colic,  renal  colic,  uterine  cramps  and  bronchial  asthma. 
Holzknecht  and  Saglitzer  and  others  in  x-ray  work  noted  that  a 
dose  by  mouth  of  i  grain  (0.06  gm.)  relaxed  the  pylorus,  and 
proposed  it  for  the  differential  diagnosis  of  pylorospasm  from 
pylorostenosis.  Others  then  employed  it  in  the  treatment  of 
pyloric  spasm.  Hess,  in  testing  three  infants  with  pylorospasm 
with  repeated  \  grain  (o.oi  gm.)  doses  subcutaneously,  found  by 
roentgen  rays  that  it  diminished  the  vomiting  and  markedly 
hastened  the  passage  of  both  small  and  large  bismuth  pills  through 
the  pylorus,  but  it  delayed  their  passage  through  the  small 
intestine. 

Macht  and  Geraghty  reported  its  local  value  in  ureteral  stone, 
and  Walther  and  Fowler  each  report  3  cases  of  relief  of  pain  and 
the  passage  of  the  stone  after  the  ureteral  instillation  of  45  to 
75  minims  (3-5  c.c.)  of  a  2  per  cent,  solution. 

2.  To  overcome  vomiting,  Pal  recommends  it  in  seasickness,  and 
in  the  hyperemesis  of  pregnancy  and  after  anesthesia  or  morphine. 

3.  To  overcome  arterial  spasm,  as  in  angina  pectoris  and  the 
arterial  crises  of  arteriosclerosis  and  tabes.     Pal  considers  it  of 
no  value  in  chronic  hypertension  cases. 

4.  To  overcome  cough,  as  a  substitute  for  codeine  or  heroine. 

DI-ACETYL  MORPHINE 

Di-acetyl  morphine,  or  heroine,  of  which  the  hydrochloride, 
soluble  in  alcohol  and  water,  is  in  use,  is  somewhat  like  codeine, 
its  powers  to  diminish  pain  and  to  promote  sleep  being  less  than 
those  of  morphine,  while  its  tendency  to  produce  reflex  excitability 
is  greater.  It  is  excreted  partly  by  the  kidneys  and  partly  by  the 
intestines. 

In  Hcinz's  rabbit  experiments,  ^  grain  (o.ooi  gm.)  caused  a 
reduction  of  the  respirations  from  120  to  18  in  forty  minutes  and 
reduced  the  volume  of  air  inspired  from  880  c.c.  per  minute  to 
240  c.c.  Hence  the  individual  inspirations  are  increased  in  depth, 
but  the  respiration  is  so  slowed  that  the  intake  of  air  is  consider- 
ably reduced.  It  is  about  five  times  as  depressing  to  the  respi- 
ration as  morphine,  and  Heinz  says  that  it  is  about  thirty  times 
as  depressing  as  codeine;  while  Gottlieb  and  Magnus  state  that 
even  very  small  closes  may  show  a  dangerous  effect  upon  the 
respiratory  center.  Worth  Hale  reports  it  as  depressing  to  the 
circulation. 

In  over  100  cases  of  pulmonary  tuberculosis  the  author  made 
a  clinical  comparison  of  its  action  with  that  of  codeine,  giving 


ETHYL-MORPHINE    HYDROCHLORIDE  3QI 

each  drug  many  times  to  the  same  patient.  One-twelfth  grain 
(0.005  Sm  )  °f  heroine  hydrochloride  was  compared  with  \  grain 
(0.0015  gm.)  of  pure  codeine,  or  £  grain  (o.oi  gm.)  of  heroine 
hydrochloride  with  \  grain  (0.003  g111-)  °f  codeine.  The  codeine 
proved  superior  in  its  power  to  allay  cough,  to  overcome  pain,  and 
to  promote  sleep.  In  several  cases  the  heroine  produced  nausea 
and  constipation,  and  in  one  woman  who  was  regularly  excited  by 
morphine,  heroine  produced  the  same  excitement,  while  codeine 
did  not.  Heroine  would  seem,  therefore,  to  possess  some  of  the 
undesirable  properties  of  morphine.  Its  chief  employment  is  to 
check  cough. 

The  heroine  habit.  Like  morphine,  heroine  is  the  cause  of  a 
"vicious"  habit  that  in  a  very  few  years  has  become  wide-spread. 
It  is  usually  taken  by  mouth  or  hypodermatically  or  by  snuffing. 
By  the  last  method  it  causes  nasal  congestion  followed  by  atrophy. 

1  have  one  old  patient  who  for  several  years  obtained  his  heroine 
in  certain  proprietary  cough  remedies;  he  was  easily  switched  to 
codeine  and  then  broken  of  the  habit.    Brooks  and  Mixsell  report 

2  cases,  one  taking  6  ounces  (150  c.c.)  of  "gly co-heroine,"  a  pro- 
prietary remedy,  and  the  other  10  to  15  grains  (0.7-1  gm.)  of 
heroine  per  day.     Both  were  cured  through  the  substitution  of 
codeine.     In  some  instances  the  habit  is  very  difficult  to  cure. 
Wholey   reports   a   case  using    hypodermatically  one    hundred 
\  grain  (o.oi  gm.)  tablets  a  day.    The  symptoms  after  withdrawal 
are  pains  in  shins  and  legs,  coarse  tremor  of  hands  and  fingers, 
nervousness,  headache,  insomnia,  and  stomach  discomforts.    The 
treatment  is  the  same  as  that  for  the  morphine  habit.     In  ex- 
periments with  dogs  it  has  been  shown  that  tolerance,  similar 
to  that  from  morphine,  is  readily  established. 

ETHYL-MORPHINE  HYDROCHLORIDE 

Ethyl-morphine  hydrochloride,  or  dionine,  is  soluble  in  water 
and  alcohol.  In  dose  of  \  to  i  grain  (0.003-0.06  gm.)  it  is  not  so 
sedative  as  its  composition  would  seem  to  indicate,  but  it  is  em- 
ployed more  or  less  for  cough  and  mild  pain.  It  is  analgesic  in  the 
eye,  and  has  been  extensively  employed  by  the  ophthalmologists  in 
treatment  of  deep-seated  ocular  pain.  Lloyd-Owen  finds  that  a  2 
to  5  per  cent,  solution  dropped  in  the  eye  has  scarcely  any  effect 
on  the  cornea  and  conjunctiva,  but  is  decidedly  analgesic  in  the 
presence  of  the  deep-seated  pains  of  iritis,  glaucoma,  etc.  It  does 
not  contract  the  pupil.  Several  oculists  have  reported  to  me  a 
primary  irritation  with  chemosis  lasting  an  hour  or  two.  It  is 
probable  that  its  action  is  not  local,  and  that  it  is  absorbed 
through  the  eye  to  act  on  centers. 


392  PHARMACOLOGY   AND   THERAPEUTICS 

CANNABIS 

Cannabis  is  "the  dried  flowering  tops  of  the  pistillate  plants 
of  Cannabis  saliva  (Fam.  Morocco?},  grown  in  the  East  Indies, 
and  gathered  while  the  fruits  are  yet  undeveloped  and  are  carrying 
the  whole  of  their  natural  resin."  The  biologic  assay  requires 
that  it  shall  produce  incoordination  when  administered  to  dogs 
in  dose  of  not  more  than  0.03  gm.  per  kilogram  of  body  weight. 

The  plant  is  grown  extensively  in  various  countries  for  hemp 
fiber  and  seed,  the  seed  formation  being  accompanied  by  dimin- 
ished resin  production ;  but  in  the  East  Indies  all  staminate  plants 
and  flowers  are  removed  so  as  to  prevent  setting  of  seed,  and  this 
results  in  a  greater  product  of  resin.  Under  the  names  of  bhang, 
charas,  ganja,  guaza,  hashish,  etc.,  various  preparations  of  the 
drug  are  used  in  the  East  as  habit-drugs. 

Constituents. — Ten  to  20  per  cent  of  resin,  volatile  oil,  a 
bitter  principle,  and  traces  of  the  alkaloid  cannabinine  and  other 
alkaloids.  The  activity  resides  in  the  resin,  the  active  principle 
of  which  has  not  been  isolated.  Cannabinol  is  a  mixture,  chiefly 
oil  and  resin.  The  drug  as  marketed  is  very  variable  in  strength 
and  tends  to  deteriorate. 

Preparations  and  Doses. — Cannabis,  i  grain  (0.065  g111-); 
extract,  %  grain  (o.oi  gm.);  fluidextract,  i  minim  (0.065  c.c.); 
tincture  (10  per  cent.),  10  minims  (0.65  c.c.). 

Action. — In  eastern  peoples,  among  whom  the  "hasheesh" 
habit  is  common,  it  produces  depression  of  the  highest  centers, 
setting  free  the  imagination,  and  resulting  in  an  agreeable, 
dreamy  "dolce  far  niente"  state  resembling  that  from  morphine. 
The  sensations  of  pain  and  touch  are  lessened,  the  extremities  feel 
numb,  a  state  of  indifference  to  outside  influence  comes  on,  and 
sleep  may  follow.  The  director  of  the  Insane  Asylum  at  Ab- 
bassieh,  India,  states  that  of  2564  patients,  the  insanity  in  689 
was  attributed  to  the  excessive  use  of  hashish.  There  are 
similar  reports  from  other  asylums  in  India  and  Egypt. 

In  America  there  is  generally  no  intoxication  from  therapeutic 
doses,  but  a  mild  general  depression  of  the  intellectual  and  sen- 
sory centers  of  the  cerebrum  and  quieting  of  nervous  excitability. 
Dixon  recommends  the  inhalation  of  the  vapor  as  most  soothing. 
Like  morphine,  it  may  promote  sleep  in  the  presence  of  pain. 
From  poisonous  doses,  however,  there  is  delirious  intoxication, 
and  the  patient  may  lose  self-control,  laugh,  and  talk  at  random. 
His  sense  of  time  and  distance  may  be  lost,  and  he  may  fear  im- 
pending death.  Subsequently  there  is  general  cerebral  depres- 
sion, resulting  in  sleep  or  stupor,  with  diminished  perception  of 
pain  and  muscular  relaxation.  The  heart  becomes  slow  and  weak, 


THE   ANTIHYSTERICS    (ANTISPASMODICS)  393 

and  the  pupil  is  dilated.  Very  large  doses  have  been  recovered 
from.  An  interesting  description  of  the  effects  of  a  large  dose 
upon  himself  is  given  by  H.  C.  Wood,  Sr.,  in  his  "Therapeutics, 
its  Principles  and  Practice." 

Therapeutics. — Owing  to  its  great  variability,  its  tendency 
to  deteriorate,  and  great  differences  in  individual  susceptibility 
to  its  action,  cannabis  is  very  little  employed.  A  good  prepara- 
tion of  it  may  allay  nervous  excitability,  as  after  sexual  or  al- 
coholic excesses,  may  lessen  the  pain  of  neuralgia  or  migraine, 
and  may  promote  sleep  (in  the  presence  of  pain).  As  obtainable, 
it  often  fails  to  have  any  therapeutic  effect. 


Humulus  (hops)  is  the  strobile  of  Humulus  lupulus  (Fam. 
Moraced),  bearing  the  glandular  powder  which  is  known  as  "lu- 
pulin."  Lupulin  contains  resin,  volatile  oil,  bitter  lupamaric  acid, 
and  valeric  acid.  The  unofficial  fluidextract  of  lupulin,  dose,  3 
minims  (0.2  c.c.),  is  used  as  a  bitter,  and  as  a  mild  sedative  and 
antispasmodic  in  the  treatment  of  nervousness,  restlessness,  and 
hysteria.  A  hop  pillow  or  a  poultice  made  of  steamed  hops  is 
a  convenient  method  of  applying  heat  to  the  face,  back,  or 
shoulder,  as  in  toothache  and  neuralgia;  but  its  specific  sedative 
virtues  exist  only  in  the  minds  of  the  laity.  The  hops  used  in 
the  manufacture  of  beer  contribute  to  its  hypnotic  powers. 

Lactucarium,  the  concrete  milk  juice  of  Lactuca  mrosa  (Fam. 
Composite},  is  said  to  be  narcotic,  like  opium,  but  its  action  is 
a  very  feeble  one.  The  syrup  (5  per  cent.)  made  from  the  tinc- 
ture (50  per  cent.)  is  employed  for  cough  and  as  a  sedative  for 
children;  dose,  2  drams  (8  c.c.).  Lactucarium  lozenges  are  to  be 
had  for  cough.  One  of  the  most  famous  of  the  proprietary  lac- 
tucarium  lozenges  was  found  to  contain  opium. 

THE  ANTIHYSTERICS  (ANTISPASMODICS) 

These  are  all  aromatic  carminative  drugs,  but  they  have  a 
tendency  beyond  that  of  other  carminatives  to  lessen  states  of 
nervous  instability  and  hysteria.  The  one  most  in  use  is  valerian ; 
but  asafetida,  sumbul,  musk,  and  camphor  are  also  employed. 

Valerian  contains  0.5  to  2  per  cent,  of  a  volatile  oil  which  is 
composed  of  esters  of  valeric  acid,  chiefly  the  borneol  ester.  It 
has  the  usual  effect  of  a  volatile  oil  drug,  stimulating  the  motor 
functions  of  stomach  and  intestines,  and  overcoming  flatulence 
and  colic;  and  reflexly,  and  perhaps  slightly  directly,  stimulating 
the  heart  and  the  vasoconstrictor  and  respiratory  centers.  But,  in 
addition,  it  seems  to  exert  in  a  pronounced  manner  a  stimulant 
effect  upon  the  highest  cerebral  centers,  those  wThich  exert  psychic 


394  PHARMACOLOGY   AND   THERAPEUTICS 

control,  so  that  states  of  nervousness  are  overcome.  Important 
factors  in  producing  the  cerebral  effects  seem  to  be  the  odor,  the 
taste,  and  the  volatile  oil  effect  on  the  stomach.  Free  valeric  acid 
(valerianic  acid)  and  the  non- volatile  valerates  (valerianates) , 
such  as  those  of  ammonium,  iron,  zinc,  and  quinine,  are  scarcely 
carminative  and  have  little  of  the  effect  of  the  liquid  preparations, 

Its  preparations  are  the  20  per  cent,  tincture  (made  with  alcohol 
and  water),  and  the  20  per  cent,  ammoniated  tincture  (made  with 
aromatic  spirit  of  ammonia),  dose,  i  dram  (4  c.c.).  The  borneol 
valerate  has  the  properties  of  a  volatile  oil,  and  is  sometimes  given 
in  5-  or  lo-minim  capsules. 

Musk,  of  which  the  5  per  cent,  tincture,  tinctura  moschi,  is 
official,  dose,  i  dram  (4  c.c.),  is  the  dried  secretion  from  the 
preputial  follicles  of  the  musk-ox.  Its  odor  is  a  sex  stimulant. 
It  is  very  expensive,  therefore  its  use  in  medicine  is  limited  to 
refractory  cases  of  hiccup  and  of  manifestations  of  hysteria. 

DRUGS    WHICH    CHIEFLY    AFFECT    THE    PERIPHERAL 
NERVOUS   SYSTEM 

I.  Those  which  depress  the  peripheral  nervous  system — the 
belladonna  group,  cocaine,  etc. 

II.  Those  which  stimulate  the  peripheral  nervous  system — pilo- 
carpus  (jaborandi),  physostigma,  etc.     We  have  already  spoken 
of  adrenaline,  which  stimulates  sympathetic  nerve-endings. 

BELLADONNA  GROUP 

The  belladonna  group  includes  belladonna  (deadly  night- 
shade), stramonium  (jimson-weed  or  thornapple),  and  hyoscya- 
mus  (henbane),  all  of  which  belong  to  the  potato  family,  the 
Solanacca,  and  have  similar  constituents  and  related  pharma- 
cologic  actions. 

Occurrence. — Belladonna  (Atropa  belladonna)  is  a  purple- 
flowered  herb  of  central  and  southern  Europe  and  western  Asia. 
It  is  cultivated  for  the  market  in  England  and  Germany.  Stra- 
monium (Datura  stramonium),  also  known  as  thornapple  and 
jimson-weed,  is  a  tall,  coarse,  narcotic  smelling  herb,  which  fruits 
with  a  spiny,  four-valved  capsule  the  size  of  a  walnut,  filled  with 
small  black  seeds.  It  grows  in  Asia,  Europe,  and  the  United 
States  east  of  the  Mississippi,  and  may  be  found  in  abundance 
in  the  vacant  lots  of  our  eastern  cities.  Poisoning  from  the 
swallowing  of  the  seeds  by  children  has  frequently  been  reported. 
Hyoscyamus  (Hyoscyamus  nigcr)  is  an  herb  native  to  Europe  and 
more  or  less  cultivated. 


BELLADONNA   GROUP 


395 


Constituents. — The  active  principles  are  alkaloids,  the  chief 
of  which  are  atropine,  hyoscyamine,  and  hyoscine.  Atropine  is 
a  compound  of  equal  amounts  of  the  isomers,  dextro-  and  levo- 
hyoscyamine,  into  which  it  separates  when  dissolved  in  water. 
Hyoscyamine  is  levo-hyoscyamine,  and  is  readily  changed  to 
dextro-hyoscyamine.  In  the  growing  belladonna  the  hyoscya- 
mine is  said  to  form  in  the  young  leaves,  to  be  later  changed  to 
atropine. 

According  to  the  predominance  of  one  or  other  of  these  alka- 
loids, and  to  the  amounts  present,  the  drugs  of  this  group  fall 
into  a  regular  pharmacologic  series,  as  follows: 

i.  Belladonna  (root  and 
leaves) — the  leaves  contain 
0.35  per  cent.,  and  the  root, 
0.5  per  cent.,  of  alkaloid, 
which  is  nearly  all  atropine. 
It  has,  therefore,  a  typical 
atropine  action. 


Fig.   46. — Datura    stramonium,    Linne 
— flowering  branch  (Maisch). 


Fig.  47. — Capsule  of  stramonium 
(Bastin).  The  seeds  have  frequently 
been  the  cause  of  poisoning. 


2.  Stramonium  (leaves)  contains  0.35  per  cent,  of  alkaloid, 

mostly  hyoscyamine,  but  with  small  amounts  of  atropine 
and  hyoscine.  It  is  less  stimulating  to  the  cerebrum  and 
may  be  narcotic. 

3.  Hyoscyamus  (leaves)  contains  (0.065  Per  cent-  °f  alkaloid, 
mostly  hyoscyamine,  with  a  fair  amount  of  hyoscine,  and  only 
traces  of  atropine.     It  is  rather  narcotic,  but  is  weaker  than  the 
other  drugs  of  the  group. 

Preparations  and  Doses. — The  dose  of  belladonna,  or  stra- 
monium is  i  grain  (0.06  gm.);  that  of  hyoscyamus,  4  grains 
(0.25  gm.).  The  doses  of  the  preparations  can  readily  be  esti- 


396  PHARMACOLOGY   AND   THERAPEUTICS 

mated  from  their  known  strengths.     The  official  preparations 
are: 

The  fluidextracts  and  extracts  of  belladonna  (fluidextract  of 
root,  extract  of  leaves)  and  of  hyoscyamus,  and  the  extract 
of  stramonium. 

The  10  per  cent,  tinctures  of  belladonna  leaves,  of  stramo- 
nium, and  of  hyoscyamus. 
In  addition: 

Of  belladonna,  the  liniment  is  made  by  adding  5  per  cent,  of 

camphor  to  the  fluidextract;  and  preparations  of  the  extract 

are:  the  ointment,  10  per  cent.;  the  plaster,  30  per  cent.; 

and    the    unofficial    rhinitis   tablets,    which   have   various 

formulae.     The  formula  given  to  the  author  by  Dr.  R.  P. 

Lincoln,  the  originator  of  rhinitis  tablets,  is:  extract  of 

belladonna,  gr.  -g-  (0.007  gm.),  camphor,  gr.  \  (0.015  gm-)> 

and  quinine  bisulphate,  gr.  \  (0.03  gm.).   Another  formula 

is :  camphor  and  quinine  sulphate  or   bisulphate,  of  each, 

\  grain  (0.03  gm.),  and  fluidextract  of  belladonna,  \  minim 

(0.015  c.c.).      They  are  often  prescribed  "half  strength." 

Of  stramonium,  the  ointment  contains  10  per  cent,  of  extract. 

Of  the  alkaloids,  the  dose  is  yi^  grain   (0.0004  gm-)>  the 

maximum  beginning  dose  being  ^V  grain   (0.0012  gm.).     The 

official  salts  are:  atr opine  sulphate,  hyoscyamine  hydrobromide, 

hyoscyamine  sulphate,  and  scopolamine  hydrobromide   (hyoscine 

hydrobromide),  all  readily  soluble  in  water  and  alcohol.     Atropine 

can  withstand  the  heat  of  boiling  water  without  decomposition. 

Hyoscine  and  scopolamine  are  chemically  identical,  and  in  spite 

of  claims  to  the  contrary,  are  considered  by  pharmacologists  to 

be  physiologically  identical. 

Pharmacologic  Action  of  Atropine. — The  primary  actions  of 
the  group  are  those  of  atropine.  They  are — (a)  To  stimulate 
nerve-centers,  and  (b)  to  depress  nerve-endings. 

(a)  The  nerve-centers  which  atropine  primarily  stimulates, 
are   the   cerebral   and    the   vital   medullary   centers.     Only   in 
highly  poisonous  doses  does  it  depress  these. 

(b)  The  nerve-endings  which  atropine  primarily  depresses  are: 

1.  The  sensory  nerve-endings — not  a  marked  effect,  but  tend- 
ing to  lessen  sensation  and  pain.     Short  and  Salisbury  (1910) 
could  not  detect  any  cutaneous  anesthesia. 

2.  The  motor  nerve-endings  in  the  smooth  muscle  of  the  viscera 
(not  in  striated  muscle  and  arterial  muscle) — a  strong  effect, 
tending  to  allay  abnormal  contraction  of  the  muscles  of  the 
viscera  (bronchi,  stomach,  intestines,  bile-ducts,  etc.). 

3.  The  secretory  nerve-endings — a  very  strong  effect,  tending 
to  check  the  mucous,  digestive,  and  skin  secretions. 


BELLADONNA    GROUP  397 

4.  The  ends  of  the  third  nerve  in  the  eye— a.  strong  effect. 

5.  The  vagus  nerve-endings — so  that  the  heart  is  freed  from 
the  usual  inhibitory  vagus  control — an  effect  that  is  striking 
but  short-lived. 

Atropine  depresses  primarily  these  nerve-endings,  whether 
it  is  applied  locally  or  given  internally,  while  it  has  no  effect 
at  all  upon  most  protoplasmic  structures.  It  is,  therefore,  a 
highly  selective  drug.  In  speaking  thus  of  nerve-endings  from 
a  practical  point  of  view,  it  should  be  noted  that  atropine  acts 
on  muscle  after  nerve  degeneration,  though  not  on  the  contractile 
substance  of  the  muscle ;  hence  it  probably  affects  some  material 
which  acts  as  the  receptor  of  the  nerve  impulse.  It  is  some  part 
of  the  neuromuscular  junction,  though  we  speak  of  it  crudely 
as  the  nerve-ending. 

Absorption  and  Local  Action. — There  is  slight  absorption  from 
plasters,  and  fair  absorption  from  oily  and  alcoholic  preparations, 
as  ointments  and  liniments;  so  the  drug  may  have  an  effect 
through  the  skin  on  sensory  and  secretory  nerve-endings.  In 
tests  with  66  belladonna  and  scopola  plasters  Bastedo  and  Martin 
(1901)  found  that  these  had  distinctly  more  power  to  stop  pain 
than  had  the  simple  plaster  without  belladonna.  That  there  is 
some  absorption  from  the  plasters  is  shown  further  by  the  oc- 
casional occurrence  of  poisoning  from  them.  (See  Fig.  51.) 
Absorption  is  ready  through  mucous  membranes,  the  drug  rapidly 
disappearing  from  stomach  and  duodenum. 

Alimentary  Tract. — The  chief  effects  of  the  drug  are  to  lessen 
secretion  and  overcome  colic  (spasmodic  contraction  with  pain). 
The  taste  is  bitter. 

(a)  Secretion. — After  atropine,  stimulation  of  the  chorda 
tympani  results  in  no  secretion  of  saliva.  This  is  not  due  to  the 
paralysis  of  the  center  or  ganglia,  for  stimulation  of  the  nerve 
peripheral  to  the  ganglia  still  produces  no  secretion.  Stimula- 
tion of  the  sympathetic,  however,  continues  to  cause  secretion 
and  vasodilatation,  hence  there  is  no  paralysis  of  the  secreting 
cells  themselves  or  of  the  vasodilating  fibers.  Therefore  the 
paralyzed  portion  is  the  connection  between  the  nerve  and  the 
secreting  cell,  i.  e.,  the  nerve-ending.  There  is  some  evidence 
that  in  large  amounts  atropine  slightly  depresses  the  secretory 
cells  themselves. 

In  the  mouth  the  saliva  arid  mucous  secretions  are  lessened, 
and  the  throat  and  mouth  become  dry,  an  effect  which  is  often 
noticed  from  quite  small  doses.  If  marked,  the  patient  cannot 
swallow,  though  he  may  be  very  thirsty.  The  stomach  secre- 
tion is  less  affected,  but  is  probably  moderately  diminished 


398  PHARMACOLOGY  AND  THERAPEUTICS 

by  very  large  doses.  Riegel  states  that  this  is  especially  true  of 
the  acid  portion  of  the  gastric  juice. 

The  intestinal  secretions  tend  to  be  lessened. 

The  secretion  of  the  pancreas,  though  under  the  influence  of  the 
vagus,  is  dependent  on  the  presence  in  the  blood  of  the  chemic 
substance  secretin,  rather  than  on  nerve  impulses,  so  atropine 
has  little  if  any  direct  effect  upon  the  amount  of  its  digestive 
elements.  But  through  depression  of  the  vagus  endings  it  may 
lessen  the  watery  portion  of  the  secretion. 

The  bile  production  has  been  shown  also  to  be  due  partly 
to  a  substance  in  the  blood,  probably  secretin,  and  its  production 
is  little,  if  any,  affected. 

It  was  formerly  believed  that  by  cutting  off  certain  nerve 
impulses  which  induce  the  change  of  glycogen  to  sugar,  atropine 
promoted  the  storing  of  glycogen  by  the  liver,  therefore  it  was  rec- 
ommended by  Rudisch  (1909)  in  diabetes.  Forchheimer  (1911) 
says  of  it:  "In  a  large  number  of  cases  glycosuria,  and  with  it 
acetone  bodies,  have  diminished  or  disappeared."  But  in  the 
very  careful  studies  of  two  diabetics  by  Mosenthal  (1912) 
atropine  sulphate  in  amounts  which  gave  beginning  poisonous 
symptoms,  i.  e.,  up  to  T-g-g-  grain  (0.0045  gm-)  three  times  a  day, 
showed  absolutely  no  effect  on  the  carbohydrate  tolerance. 

(b)  Motor  Activity. — In  the  stomach,  atropine  tends  to  over- 
come spasmodic  contraction  of  the  pylorus,  but  only  when  given 
in  large  doses  hypodermatically.  Indeed,  Ochsenius  in  Czerny's 
clinic  found  that  in  a  child  of  one  month  it  required  ¥^  to  ^  grain 
(0.75  to  0.9  mg.)  of  atropine  a  day  to  relax  the  pylorus. 

In  the  intestines,  atropine  lessens  but  does  not  abolish  the 
vagus  power  (the  vagus  is  the  motor  nerve  of  the  small  intestine), 
so  that  the  effects  of  drugs  which  act  as  cathartics  by  stimulation 
of  the  vagus,  e.  g.,  physostigmine,  may  be  checked;  while  the 
peristalsis  from  cathartics  which  act  by  direct  irritation  of  the 
intestinal  wall,  and  not  through  the  vagus  nerves,  is  apparently 
not  affected.  This  is  because  atropine  does  not  affect  the  auto- 
matic motor  ganglia  of  Auerbach's  plexus.  (See  Fig.  2,  page  120.) 
It  tends,  however,  to  check  the  so-called  "tone-waves"  without 
checking  peristalsis;  and  when  from  overirritation  or  from  vagus 
overactivity  there  is  spasmodic  contraction  with  colicky  pains, 
or  spastic  constipation,  atropine  tends  to  overcome  this.  To 
understand  this  action  we  must  understand  the  difference  between 
normal  peristalsis  and  intestinal  colic. 

In  peristalsis  a  wave  of  contraction  precedes  the  stimulating 
body  in  the  intestine  by  about  an  inch,  while  the  bowel  relaxes 
below  the  stimulating  body  for  a  foot  or  two.  That  is  to  say, 
peristalsis  is  a  coordinated,  purposeful  action  involving  both 


BELLADONNA   GROUP 


399 


stimulation  and  inhibition.  It  is  designed  to  propel  the  intestinal 
contents  forward  and  bring  them  into  contact  with  the  intestinal 
juices.  But  if,  instead  of  this  coordinated  wave  of  contraction 
and  relaxation,  there  is  a  spasmodic  contraction  of  the  intestine 
about  some  offending  body,  even  about  an  accumulation  of  gas, 
or  preceding  an  obstruction  that  cannot  be  moved  onward,  there 
is  intestinal  colic  or  cramp;  at  the  same  time  the  contents  are 
not  propelled  along,  so  there  is  constipation.  In  such  a  case 
atropine,  by  allaying  the  spasm,  may  permit  normal  peristalsis 
to  be  restored,  and,  as  a  consequence,  cause  a  disappearance  of 
both  the  cramp  and  the  constipation.  Irritant  cathartics  some- 


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Fig.  49. — Chart  showing  the  effects  of  atropine  on  the  heart-rate  of  a  patient 
with  vagus  slowing  from  digitalis.  The  numbers  at  the  side  represent  pulse  beats, 
those  at  the  top,  minutes  (James  Mackenzie,  in  "Heart,"  vol.  ii.  No.  4,  1911). 

times  cause  this  kind  of  colic,  i.  e.,  they  tend  to  gripe,  and  to  these 
atropine  or  one  of  the  extracts  is  frequently  added  as  a  corrective. 
The  constipation  and  colic  of  peritoneal  irritation,  anemia,  lead 
poisoning,  or  fecal  impaction  may  be  overcome  by  atropine, 
but  if  the  obstruction  is  immovable,  i.  e.,  of  surgical  nature, 
atropine  obviously  has  no  value. 

Heart. — The  vagus  center  is  stimulated,  but  any  effect  from 
this  is  soon  prevented  by  depression  of  the  vagus  nerve-endings, 
so  that  from  large  doses  there  regularly  results  a  faster  and  some- 
what stronger  heart-beat.  In  the  mammal  no  direct  action  upon 
the  muscle  is  distinguished,  though  in  the  frog  a  dose  of  atropine 
will  temporarily  revive  an  exhausted  heart.  The  largest  dose 


400  PHARMACOLOGY   AND   THERAPEUTICS 

ordinarily  employed  for  humans  hypodermatically  is  -£$  grain 
(0.0012  gm.);  its  effect  on  the  vagus  is  seen  in  about  twenty 
minutes,  and  lasts  less  than  one  hour.  (See  Fig.  49.)  This 
vagus  effect  shows  both  at  the  sinus  node  and  at  the  auriculo- 
ventricular  node.  Atropine  is  thus  able  to  check  a  heart-block 
brought  about  by  digitalis,  and  to  annul  the  valuable  action  of 
digitalis  in  auricular  fibrillation.  In  one  case  (Laslett)  of 
standstill  of  the  whole  heart  with  pauses  of  five  to  eight  seconds, 
atropine  restored  the  normal  rhythm  by  cutting  off  the  vagus 
effect  on  the  sinus  node. 

Arteries. — The  vasoconstrictor  center  is  slightly  stimulated, 
and  this,  with  the  increased  rate  of  the  heart,  causes  a  rise  in 
arterial  pressure.  This  is  easily  demonstrated  in  a  dog.  The 
contraction  of  the  arteries  is  most  marked  in  the  splanchnic  area. 
In  man,  however,  the  rise  in  blood-pressure  from  even  maximal 
therapeutic  doses  is  usually  inappreciable,  and  if  present  is 
entirely  due  to  the  increased  heart-rate  (Sollmann  and  Pilcher). 
Berezin  found  no  effect  on  the  pulmonary  vessels.  In  poisoning 
the  vasoconstrictor  center  tends  to  be  depressed. 

The  Cutaneous  Arterioles. — From  poisonous  amounts  the 
arteries  of  the  skin,  especially  those  of  the  head  and  neck,  are 
dilated;  and  a  flushed  face  or  an  erythematous  rash  like  that  of 
scarlet  fever  is  characteristic  of  atropine  poisoning.  The  flushed 
skin  is  from  a  central  action,  as  there  is  no  flushing  if  the  sympa- 
thetic in  the  neck  is  divided. 

The  Blood. — It  has  been  stated  that  the  eosinophiles  are  in- 
creased in  number,  but  Herrick  found  this  not  to  be  the  case  in 
the  guinea-pig. 

Respiration. — A  large  dose  of  atropine  is  followed  by  deeper 
and  more  rapid  breathng  and  a  considerable  increase  in  the 
amount  of  air  inspired.  This  is  largely  due  to  stimulation  of  the 
respiratory  center.  There  is  probably  also  depression  of  the 
motor  endings  of  the  vagus,  resulting  in  dilatation  of  the  bronchi, 
and  depression  of  the  sensory  ends  of  the  vagi  in  the  bronchi,  for 
stimuli  through  these  usually  slow  respiration.  In  a  number  of 
cases  the  author  failed  to  obtain  a  change  in  the  rate  of  respira- 
tion from  hypodermatic  injections  of  -^  and  J7  grain  (1-1.3  mg-)- 
Edsall  and  Means  by  doses  large  enough  to  cause  marked  in- 
crease in  pulse-rate  were  unable  to  affect  the  breathing  in  Cheyne- 
Stokes  respiration  due  to  cerebral  hemorrhage;  but  in  a  normal 
human  obtained  decided  stimulation  from  a  dose  that  produced 
toxic  symptoms.  Higgins  and  Means  go  so  far  as  to  say  that 
any  effect  on  the  respiration  is  due  to  dilatation  of  the  bronchi 
and  increased  metabolism. 

The  drug  is  much  used  in  narcotic  poisoning,  especially  that 


BELLADONNA   GROUP  4OI 

from  morphine.  Vollmer  (1892)  reported  that  a  dog  inspiring 
4500  c.c.  of  air  per  minute  was  given  i  grain  (0.06  gm.)  of  morphine 
sulphate  at  8.45.  At  3.40  the  air  inspiration  was  4000  c.c.  Then 
-£$  grain  (0.003  S111-)  °f  atropine  was  given,  and  in  fourteen  minutes 
the  inspiration  was  6000  c.c.;  in  twenty-one  minutes,  10,000  c.c. 
But  excessive  doses  exhaust  the  center,  and  must  be  guarded 
against  in  the  use  of  the  drug  as  an  antidote.  Exhaustion  of 
the  center  is  the  cause  of  death. 

The  secretions  of  nose,  throat,  and  bronchi  are  diminished, 
so  that  the  membranes  are  dry  and  the  mucus  thick  and  tenacious. 
Excessive  contraction  of  the  bronchial  muscles,  as  in  spasmodic 
asthma,  is  overcome  by  depression  of  the  bronchomotor  vagal 
nerve-endings. 

Cerebrum. — The  effect  from  therapeutic  doses  is  very  little, 
but  after  poisonous  amounts  there  is  psychic  stimulation,  and  the 
patient  becomes  talkative  and  wakeful,  without  any  pronounced 
intellectual  stimulation  like  that  from  caffeine.  The  poisoning 
may  go  on  to  a  delirium,  usually  of  cheerful,  loquacious  type, 
and  may  even  result  in  maniacal  excitement.  Cerebral  depres- 
sion does  not  generally  ensue  until  the  centers  have  become  ex- 
hausted, and  then  there  may  follow  mental  confusion  and  nar- 
cosis leading  to  sleep,  stupor,  and  coma.  In  therapeutic  amounts 
the  drug  is  not  a  narcotic. 

The  motor  areas  are  also  stimulated  by  poisonous  doses,  as 
shown  by  the  increased  response  to  electric  stimulation  of  the 
exposed  brain  and  by  the  restless  activity.  The  general  ex- 
hilaration observed  after  overdoses  is  known  as  the  "belladonna 
jag,"  but  though  it  superficially  resembles  that  from  alcohol, 
it  is  true  stimulation,  as  shown  by  the  increased  excitability  of 
the  motor  areas  and  the  larger  doses  of  narcotic  necessary  to 
depress  the  intellectual  powers. 

The  medulla,  after  large  hypodermatic  doses,  shows  stimula- 
tion of  the  respiratory  center,  with  weak  stimulation  of  vagus 
and  vasoconstrictor.  Death  takes  place  from  exhaustion  and 
paralysis  of  the  respiratory  center. 

The  spinal  cord  is  stimulated  by  large  doses,  the  increase  in 
reflex  excitability  being  manifested  by  twitching  of  the  muscles. 
In  the  late  stages  of  poisoning  twitching  may  also  result  from 
asphyxia. 

The  peripheral  nerves  have  already  been  spoken  of. 

Comparing  atropine  with  caffeine  and  strychnine  as  central 
stimulants,  we  might  say  that,  in  therapeutic  doses,  all  three 
stimulate  the  medullary  centers,  and  of  these  chiefly  the  re- 
spiratory; but  that  caffeine,  in  addition,  stimulates  the  intel- 
lectual functions,  and  strychnine  the  spinal  or  reflex  functions. 
26 


402  PHARMACOLOGY   AND   THERAPEUTICS 

Eye. — Atropine  has  four  important  effects  on  the  eye:  It 
dilates  the  pupil,  paralyzes  accommodation,  increases  intra- 
ocular tension,  and  lessens  pain. 

(a)  The  Dilatation  of  the  Pupil. — The  iris  consists  of  two  sets 
of  muscles — the  circular,  supplied  by  the  third  nerve,  and  the 
radial,  supplied  by  the  sympathetic  fibers  from  the  superior 
cervical  ganglion.  These  two  sets  of  muscles  are  in  constant 
action,  and  by  opposing  each  other  constitute  an  exceedingly 
sensitive  balanced  mechanism  for  the  regulation  of  the  size  of 
the  pupil.  Dilatation  of  the  pupil  may  result  from  circular 
depression  or  radial  stimulation;  contraction  of  the  pupil  from 
circular  stimulation  or  radial  depression,  and  these  stimulations 
or  depressions  may  be  of  center,  ganglia,  nerve-endings,  or 
muscle-fibers. 


Fig.  50. — Increased  convexity  of  the  lens  during  accommodation.  The  solid 
white  outline  of  the  lens,  /,  shows  its  form  when  relaxed.  The  dotted  line  shows 
the  increased  curvature  of  the  anterior  surface  during  accommodation,  and  its 
advancement  forward  into  the  anterior  chamber,  a.  z  is  the  suspensory  ligament; 
m,  the  ciliary  muscle;  and  i,  the  iris  (Landolt). 

When  a  i  per  cent,  aqueous  solution  of  atropine  sulphate  is 
dropped  in  a  man's  eye,  the  pupil  dilates  in  about  fifteen  or  twenty 
minutes,  but  takes  two  hours  more  to  reach  the  maximum  dila- 
tation. There  is  no  effect  on  the  other  eye.  If  atropine  is  in- 
jected into  an  excised  mammal  eye,  the  pupil  dilates,  and  if  an 
animal  is  atropinized,  stimulation  of  the  third  nerve,  either 
central  or  peripheral  to  the  ciliary  ganglia,  is  without  effect  on 
the  pupil.  The  action  is,  therefore,  a  purely  peripheral  one. 
But  it  is  not  a  direct  effect  upon  the  muscle,  for  in  the  atropinized 
animal  direct  stimulation  of  the  circular  muscle  results  in  con- 
traction; therefore  the  site  of  the  paralyzing  action  of  the  drug 
must  be  confined  to  the  third-nerve  endings  or  the  neuromuscular 
junction. 


BELLADONNA   GROUP  403 

The  dilatation  from  atropine  is,  therefore,  the  result  of  the 
unopposed  action  of  the  radial  muscles.  It  is,  however,  fre- 
quently strong  enough  to  break  weak  adhesions  between  cornea 
and  iris,  or  to  make  an  iris  which  is  strongly  attached  at  two 
points  bow  out  between  the  points  of  attachment.  The  pupil 
gradually  regains  its  power,  but  is  not  fully  restored  to  normal 
for  one  or  two  weeks.  That  there  is  no  stimulation  of  the  radial 
mechanism  is  evident,  for,  after  atropine,  stimulation  of  the 
cervical  sympathetic  results  in  a  still  greater  dilatation. 

A  drug  which  causes  dilatation  of  the  pupil  is  called  a  mydri- 
atic.  Belladonna  gets  its  name  from  this  mydriatic  action  (bella, 
beautiful;  donna,  lady),  which  makes  the  eye  seem  bright  and 
sparkling. 

(b)  Accommodation   depends   essentially   on    the   curvature 
of  the  crystalline  lens,  and  this  curvature  is  regulated  by  the 
ciliary  muscle.     When  the  ciliary  muscle  contracts,  the  capsule 
of  the  lens  relaxes,  and  the  elastic  lens  bulges  forward  and  be- 
comes more  convex,  i.  e.,  accommodates  for  near  objects.     But 
when  this  muscle  is  paralyzed,  the  capsule  of  the  lens  is  drawn, 
the  lens  is  more  flattened,  and  it  is  impossible  to  focus  the  sight 
on  near  objects.     A  drug  that  paralyzes  accommodation  in  this 
manner  is  a  cycloplegic.     Atropine  is  strongly  cycloplegic.     This 
effect  on  accommodation  does  not  take  place  until  some  time 
after  the  pupil  has  begun  to  dilate,  and  it  wears  off  more  quickly 
than  the  effect  on  the  pupil;  but  until  the  power  of  accommoda- 
tion is  nearly  restored,  the  patient  cannot  read  or  see  near  objects 
clearly. 

In  fitting  glasses  paralysis  of  accommodation  is  necessary. 
A  i  :  200  solution  of  atropine  sulphate  usually  paralyzes  accom- 
modation in  one  hour,  but  restoration  does  not  take  place  for 
several  days. 

(c)  Intra-ocular  Tension. — The  normal  eyeball  tension  depends 
chiefly  on  two  factors,  viz.:  (i)  The  amount  of  intra-ocular  secre- 
tion, and  (2)  the  freedom  with  which  fluids  may  escape  through 
the  efferent  lymph-channels,  i.  e.,  through  the  spaces  of  Fontana 
at  the  margin  of  the  pupil,  into  the  canal  of  Schlemm.     The 
tension  may  be  raised  either  by  extra  secretion  or  by  dilatation 
of  the  pupil  which  results  in  shutting  off  the  spaces  of  Fontana. 
It  is  by  dilatation  of  the  pupil  that  atropine  causes  the  increase 
of  tension.     In  glaucoma,  a  disease  in  which  the  tension  is  al- 
ready high,  atropine  may  produce  a  dangerous  condition;  and 
even  when  there  is  merely  a  glaucomatous  tendency,  it  may  pre- 
cipitate an  attack  of  glaucoma. 

(d)  Pain. — Atropine  gives  moderate  relief  from  the  pains  of 
iritis  and  other  intra-ocular  inflammations. 


404  PHARMACOLOGY   AND   THERAPEUTICS 

Since  atropine  is  highly  selective,  the  same  ocular  effects 
may  be  seen  after  the  internal  administration  of  large  doses. 
An  antagonist  of  atropine  is  physostigmine,  which  stimulates  the 
ends  of  the  third  nerve.  It  is  not  powerful  enough  to  remove 
the  effects  of  atropine  at  once,  but  greatly  lessens  the  time 
which  the  eye  takes  to  return  to  normal. 

Muscles. — Probably  no  direct  action.  The  smooth  muscle 
of  the  viscera  is  weakened  by  the  depression  of  motor  nerve- 
endings  mentioned  above. 

Secretions. — Those  of  the  alimentary  tract  have  already  been 
spoken  of.  No  drug  has  greater  power  to  check  the  sweat  and 
mucous  secretions.  It  does  not  directly  affect  the  amount  of 
bile  or  urine. 

Sweat. — Stimulation  of  the  sciatic  nerve  of  a  normal  cat 
regularly  induces  sweating  of  the  foot.  In  an  atropinized  animal 
sweating  cannot  be  induced.  The  profuse  sweating  of  pilocarpine 
is  checked  by  atropine,  also  the  sweating  from  certain  other  drugs, 
such  as  aspirin  and  phenacetin;  also  the  night-sweats  of  tuber- 
culosis. 

Milk. — After  all  the  nervous  connections  are  severed,  the 
breasts  still  have  the  power  to  secrete  milk,  though  the  secre- 
tion is  less  in  amount.  Hence  atropine,  which  merely  cuts  off 
the  nervous  influences,  tends  to  reduce  the  milk  secretion  very 
little,  and  cannot  cause  the  complete  stoppage  of  the  secretion. 
The  drug  acts  when  applied  to  the  breasts,  as  well  as  when  taken 
by  mouth. 

Temperature. — In  poisoning  it  is  characteristic  that  the 
temperature  may  rise  several  degrees.  The  author  saw  a  case 
with  a  temperature  of  106°  F.  (41.1°  C.).  According  to  Ott,  this 
is  due  to  the  absence  of  sweating,  for  no  rise  of  temperature 
takes  place  in  animals,  such  as  dogs,  which  do  not  sweat,  and 
are  therefore  not  dependent  upon  sweating  as  a  means  of 
lowering  temperature.  Others  think  it  is  an  effect  upon  the 
heat-regulating  centers.  (See  Cocaine.) 

Elimination. — A  considerable  portion  of  the  drug  is  oxidized, 
the  remainder  being  eliminated  rapidly  by  the  kidneys.  It  is 
said  to  disappear  from  the  body  inside  of  thirty-six  hours,  but 
the  prolonged  effect  on  the  eye  indicates  that  some  is  retained 
in  that  location. 

Urinary  Organs. — The  effect  from  therapeutic  doses  on  the 
amount  of  urine  is  uncertain  and  unimportant;  but  in  poisoning, 
both  suppression  and  retention  are  reported.  As  the  urine  is  a 
weak  solution  of  atropine,  it  will  exert  a  remote  local  action  in 
the  urinary  tract  to  lessen  pain  and  spasm.  In  poisoning,  the 
urine,  concentrated  by  boiling,  will  dilate  the  pupil  of  an 


Fig-  S1- — (General  eruption  following  application  of  a  belladonna  plaster  (W.  S. 
Gottheil  in  Archives  of  Diagnosis). 


BELLADONNA   GROUP  405 

animal's  eye;  hence  this  may  be  employed  as  a  test  for  the 
poison. 

Tolerance. — To  a  certain  degree  tolerance  may  be  set  up  in 
man  by  gradual  increase  in  the  dosage,  so  that  as  much  as  |  grain 
(0.03  gm.)  may  be  borne  without  ill  effects.  Children  can  take 
proportionally  large  doses;  in  fact,  a  child  of  eight  may  be  given 
the  same  dose  as  an  adult.  I  have  seen  a  man  of  forty-five  more 
affected  by  doses  of  10  minims  (0.60  c.c.)  of  the  tincture  of  bella- 
donna than  was  his  son  of  eight  by  the  same  amount.  Among 
subhuman  mammals  it  is  found  that  the  carnivora  are  especially 
susceptible  to  the  drug,  while  the  herbivora  are  markedly  resistant. 
A  cat,  for  instance,  is  readily  poisoned,  while  a  horse  or  a  rabbit 
may  feed  on  belladonna  leaves  with  comparative  impunity,  though 
their  flesh  becomes  poisonous  to  the  carnivora.  Successive  lit- 
ters of  healthy  rabbits  have  been  reared  entirely  on  belladonna 
and  stramonium  leaves,  and  Calmus  found  that  it  took  about  15 
grains  (actually  0.972  gm.)  of  atropine  to  kill  a  small  rabbit.  In 
rabbit's  serum  Doblin  and  Fleishmann  have  found  a  ferment 
which  annuls  the  toxic  action  of  atropine. 

Toxicology. — In  practice,  the  dilated  pupil,  the  dry  throat, 
and  mild  cerebral  symptoms  are  the  regular  warnings  of 
overdosage.  In  full  poisoning  there  is  a  stage  of  central  stimu- 
lation followed  by  collapse.  In  this  stage  of  stimulation  the 
skin  is  warm  and  dry;  the  face  and  neck  are  flushed,  either 
uniformly  or  in  blotches,  to  resemble  the  skin  of  scarlet  fever; 
the  pupils  are  widely  dilated,  and  accommodation  paralyzed, 
so  that  vision  is  disordered;  the  throat  is  very  dry  and  red, 
and  there  is  a  feeling  of  constriction,  so  that  swallowing,  even  of 
water,  is  difficult,  though  the  patient  may  be  thirsty;  the  breath 
is  foul;  the  pulse  is  rapid,  with  arterial  pressure  above  normal; 
respiration  is  rapid  and  deep;  the  patient  is  wide-awake,  excit- 
able, restless,  and  loquacious  or  overcheerful,  and  may  pass  into 
a  chattering  delirium  with  confused  ideas,  or  even  into  a  condi- 
tion resembling  mania.  The  temperature  may  rise  several 
degrees.  The  concentrated  urine  dropped  in  a  cat's  eye,  two 
drops  every  five  minutes,  will  dilate  the  pupil.  Belladonna 
poisoning  has  been  mistaken  for  scarlet  fever  and  for  acute 
mania;  with  the  latter  diagnosis  patients  have  been  confined 
in  asylums  for  the  insane. 

Following  this  stage  of  stimulation  comes  collapse,  with  heart 
very  feeble,  blood-pressure  low,  respiration  slow  and  shallow, 
etc.  The  warm,  dry  skin  may  change  to  a  cold,  clammy  one, 
and  death  take  place  from  failure  of  respiration. 

A  single  dose  of  y^  grain  (0.0006  gm.)  of  atropine  sulphate 
will  in  some  patients  cause  dryness  of  the  throat  and  dilated 


406  PHARMACOLOGY  AND  THERAPEUTICS 

pupil;  -gV  grain  (0.0012  gm.)  has  produced  the  delirium,  ^  grain 
(0.03  gm.)  has  proved  fatal,  and  3  grains  (0.2  gm.)  have  been 
recovered  from.  Poisonous  symptoms  have  followed  the  use  of 
atropine  in  the  eye. 

Atropine  may  remain  in  the  dead  body  for  a  long  time  un- 
changed. This  is  of  importance  from  a  medicolegal  point  of 
view,  for  the  atropine  may  be  mistaken  for  a  ptomain,  ptomatro- 
pine,  which  has  similar  chemic  and  pharmacologic  properties. 

Treatment  of  Poisoning. — The  stomach  may  be  lavaged,  with 
or  without  a  solution  of  tannic  acid  or  tea  (Sollmann  says  that  tea 
is  an  inferior  precipitant  for  alkaloids).  For  the  delirium  and 
mania  an  ice-cap  may  be  applied  to  the  head,  whisky  or  bromides 
administered,  and,  if  necessary,  ether  inhaled  to  lessen  the  ex- 
citement. (Morphine,  chloral,  and  chloroform  should  be  avoided 
because  of  their  tendency  to  precipitate  respiratory  failure.)  In 
the  collapse  stage  the  regular  treatment  is  that  for  severe  collapse. 
Pilocarpine  and  physostigmine  antagonize  the  atropine  action 
on  certain  nerve-endings,  but  as  the  poisoning  is  dependent 
upon  the  cerebral  and  medullary  effects,  these  peripheral  an- 
tagonists are  not  antidotes  of  any  great  value. 

Therapeutics  and  Administration. — A.  To  Diminish  Secre- 
tion.— 

1.  Of  mucus — as  in  excessive  secretion  from  nose,  throat,  and 

bronchi.  In  bronchitis,  in  the  free  running  stage  of  cold 
in  the  head,  the  rhinitis  tablets,  full  or  half  strength, 
one  every  hour  for  6  doses,  are  favorites. 

2.  Of  sweat — as  the  liniment  of  belladonna  in  sweating  of 

hands  and  feet,  and  atropine  internally  for  the  night- 
sweats  of  tuberculosis. 

3.  Of  milk — when  excessive,  or  when  it  is  desired  to  dry  up 

the  breasts — liniment  or  ointment  externally;  or  the 
drug  internally. 

4.  Of  saliva — as  in  profuse  salivation  from  any  cause — the 

drug  internally. 

5.  Of  gastric  j 'nice — as  in  hyperacidity  and  hypersecretion,  T^ 

grain  (0.0006  gm.)  of  atropine  sulphate  or  %  grain  (0.04 
gm.)  of  extract  of  belladonna  fifteen  or  twenty  minutes 
before  meals. 

B.  To  relax  over  contracted  smooth  muscle — as  in  spasmodic 
asthma  and  the  spasm  of  smooth  muscle  which  results  in  colic. 
The  latter  occurs  in  the  esophagus,  cardia  (cardiospasm) ,  pylorus 
(pylorospasm) ,  ileocecal  valve,  or  any  part  of  the  stomach  or 
intestine,  in  the  bile-passages  or  gall-bladder  (biliary  colic),  in 
the  pelvis  of  the  kidney  or  ureter  (renal  colic),  in  the  neck  of  the 
bladder,  and  in  spasmodic  dysmenorrhea  (in  this  last  mentioned 


BELLADONNA   GROUP  407 

the  drug  may  be  of  little  use  because  of  the  congestive  condition) . 
Atropine  or  extract  of  belladonna  may  be  added  to  irritant 
cathartics  as  a  corrective  to  prevent  griping. 

In  the  obstipation  which  occurs  in  lead-poisoning  and  in 
local  peritoneal  irritation  (as  in  appendicitis,  salpingitis,  or 
ovaritis,  or  renal  or  biliary  colic)  atropine  may  overcome  the 
reflex  spasm  with  resultant  catharsis.  In  intestinal  obstruction 
from  suspected  spasm,  or  in  fecal  impaction,  a  large  dose,  -fa 
grain  (0.005  g111-)^  nas  been  recommended.  But  when  there  is  a 
real  surgical  obstruction,  such  a  procedure  serves  only  to  delay 
operation,  and  sometimes  with  fatal  result. 

C.  To  depress  the  sensory  nerve-endings — to  allay  itching  (the 
liniment);  to  lessen  pain,  as  in  ulcer  of  the  leg,  anal  fissure,  or 
projecting  hemorrhoids  (the  ointment);  and  the  drug  by  mouth 
for  irritable  bladder  or  urethra,  as  in  cystitis  and  urethritis,  and 
in  enuresis  nocturna. 

D.  In  the  eye — as  a  mydriatic,  cycloplegic  and  analgesic,  for 
the  following  purposes: 

1.  To  facilitate  examination  of  the  internal  eye  posterior  to 

the  pupil. 

2.  To  paralyze  accommodation  in  fitting  glasses. 

3.  In  inflammatory  conditions  of  either  external  or  internal 

eye,  to  give  rest  to  iris  and  ciliary  muscle,  to  lessen  pain, 
and  to  prevent  the  spread  of  the  inflammation  to  the  iris ; 
and  in  iritis,  to  prevent  the  formation  of  adhesions  to  the 
lens  or  cornea,  or  to  rupture  newly  formed  adhesions. 
It  is  employed  in  |  to  i  per  cent,  solution,  and  takes  a  long 
while  for  full  dilatation.  As  the  dilatation  of  the  pupil  and 
paralysis  of  accommodation  last  several  days,  atropine  is  espe- 
cially useful  in  the  inflammatory  conditions;  while  for  examina- 
tions and  fitting  glasses  more  rapidly  acting  drugs  are  preferred. 
After  the  continued  use,  for  a  few  days,  the  return  to  normal 
may  be  delayed  for  twelve  to  fourteen  days  (de  Schweinitz), 
but  the  restoration  may  be  greatly  hastened  by  the  use  of  phy- 
sostigmine.  In  a  recent  symposium  (1916)  prominent  Amer- 
ican oculists  agreed  that,  to  avoid  the  risk  of  glaucoma,  phy- 
sostigmine  should  regularly  be  employed  after  the  use  of  atropine 
or  homatropine.  De  Schweinitz  says  that  in  the  use  of  atropine  to 
correct  errors  of  refraction  one  drop  should  be  dropped  into  the 
eye  three  times  during  the  day  preceding  the  examination;  and 
in  hypermetropic  eyes,  especially  those  with  spasm  of  accommoda- 
tion, the  drug  should  be  used  for  several  days  before  the  examina- 
tion for  refractive  errors. 

E.  In  certain  spasmodic  nervous  conditions,  as  in  whooping- 
cough  (perhaps  enuresis  nocturna  under  this  head). 


408  PHARMACOLOGY  AND  THERAPEUTICS 

F.  In  exophthalmic  goiter  (hyperthyroidism)  it  probably  acts 
by  decreasing  the  glandular  secretion.     (Sollmann  states  that 
atropine  is  antagonistic  to  thyroiodin.)     Bromides  should  be 
given  at  the  same  time,  as  the  cerebral  effects  of  belladonna  are 
undesirable  in  this  disease. 

G.  As  preliminary  to  general  anesthesia — here  it  is  of  use  to 
check  excessive  secretion  in  mouth  and  respiratory  passages,  to 
stimulate  the  respiratory  center,  and  in  chloroform  anesthesia 
to  prevent  excessive  reflex  vagus  stimulation  at  the  onset. 

H.  To  stimulate  respiration,  as  in  general  anesthesia,  in  pneu- 
monia, or  in  collapse  from  narcotic  drugs;  to  prevent  respiratory 
depression,  as  when  given  with  morphine. 

I.  To  check  excessive  vagus  action,  as  in  the  excessive  inhibi- 
tion stage  of  chloroform  anesthesia,  and  in  vagus  bradycardia  or 
partial  heart-block  from  disease  or  from  a  drug  of  the  digitalis 
group.  It  has  no  value  in  complete  and  permanent  heart-block. 
In  many  human  experiments  with  hypodermatic  doses  the 
author  was  unable  to  get  vagus  effects  with  less  than  -fa  grain 
(i  gm.).  The  effects  last  not  more  than  an  hour.  Thomas 
Lewis  (1911)  says  that  "atropine  has  never  been  known  to 
abolish  the  whole  hindrance  to  conduction." 

J.  In  anaphylaxis,  as  in  serum  sickness.  In  experiments  on 
guinea-pigs  sensitized  with  horse-serum,  Auer  (1910)  reports  that 
without  atropine  75  per  cent,  died,  and  with  atropine  only  28  per 
cent.  died. 

All  the  drugs  of  the  group,  viz.,  belladonna,  scopola,  stra- 
monium, and  hyoscyamus,  have  actions  of  the  atropine  type,  and 
can  be  used  interchangeably  for  the  ordinary  peripheral  effects. 

A  special  use  of  the  stramonium  leaves  is  in  spasmodic  asthma, 
in  which  condition  smoke  of  the  burning  leaves  is  inhaled.  The 
leaves  may  be  burned  in  a  saucer,  either  alone  or  with  other  drugs, 
or  impregnated  with  potassium  nitrate  (that  is,  saturated  with  a 
solution  of  potassium  nitrate  and  then  dried);  or  they  may  be 
added  to  tobacco,  lobelia,  or  cubebs,  and  made  into  cigars  or 
cigarettes  to  be  smoked  at  the  time  of  the  attack.  The  leaves  of 
belladonna  will  serve  as  well  as  those  of  stramonium. 

The  chief  use  of  hyoscyamus  is  as  a  sedative  in  irritable 
bladder,  cystitis,  and  gonorrhea,  and  as  a  corrective  addition  to 
irritant  cathartic  pills.  It  has  no  advantages  over  belladonna 
and  is  much  weaker. 

Hyoscyamine  (levo-hyoscyamine)  is  similar  in  action  to  atro- 
pine, which  is  a  mixture  of  levo-  and  dextro-hyoscyamine. 
Cushny  finds  that  though  it  acts  upon  the  central  nervous  system 
with  the  same  intensity  as  atropine,  it  is  nearly  twice  as  powerful 
in  its  effects  upon  nerve-endings,  especially  those  of  the  chorda 


BELLADONNA  GROUP  409 

tympani,  of  the  third  nerve  in  the  eye,  and  of  the  vagus.  It  is 
not  readily  obtained  pure,  and  is  little  employed  in  medicine. 
Dose  of  its  salts,  yi^  grain  (0.0004  gm-)- 

Hyoscine  or  scopolamine  acts  peripherally  like  atropine,  and 
therefore  will  allay  pain,  will  dilate  the  pupil,  and  will  check 
secretion.  But  its  action  in  the  eye  is  more  rapid  and  more 
powerful,  a  i  :  500  solution  dilating  the  pupil  in  ten  to  thirty 
minutes,  and  quickly  thereafter  paralyzing  accommodation, 
while  the  effect  passes  fully  away  in  three  to  five  days.  Centrally 
it  differs  from  atropine  in  that  the  period  of  cerebral  stimulation 
is  short  and  is  followed  by  prolonged  mild  depression  of  the  psy- 
chic and  motor  centers — that  is,  the  drug  is  narcotic.  It  has  a 
peculiar  amnesic  action,  at  times  completely  abolishing  the 
memory  of  events  that  occurred  during  its  action.  In  excitable 
states,  as  in  delirium  or  mania,  it  seems  to  have  great  power  to 
lessen  restlessness  or  excessive  motor  activity.  Its  use  is  not 
without  danger,  however,  for  it  shows  early  depression  of  the 
respiratory  and  vasoconstrictor  centers,  and  in  a  great  number 
of  instances  has  caused  collapse.  Eshner  and  O'Hara  report 
cases  of  collapse  after  T^T  grain  (0.0006  gm.)  of  the  hydrobromide. 
The  writer  has  seen  fatal  collapse  from  7V  grain  (0.0012  gm.) 
in  an  alcoholic  man  with  pneumonia ;  and  collapse  with  recovery 
from  2V  grain  (0.0025  £m-)  m  an  alcoholic  woman  verging  on 
delirium  tremens.  In  both  of  these  the  hyoscine  had  been 
preceded  by  ^  grain  (0.015  gm.)  of  morphine  sulphate.  Tileston 
(1913)  says  that  hyoscine  is  prone  to  be  followed  by  Babinski's 
and  Oppenheimer's  signs  and  ankle  clonus;  in  other  words,  it 
tends  to  paralyze  segments  of  the  motor  tracts.  Purves  Stewart 
describes  a  hyoscine  chorea  with  symptoms  similar  to  those  of 
ordinary  chorea.  Gregory  reports  marked  delirifacient  effects  in 
many  cases.  Collapse  is  reported  from  the  use  of  the  drug  in  the  eye. 

Its  chief  uses  are: 

1.  As  narcotic  in  the  insomnia  and  excitement  of  acute  mania, 
uremia,  and   delirium  tremens,  in   the  delirium  of  pneumonia 
(especially  in  alcoholics),  and  in  the  insomnia  of  alcoholism. 

2.  As  a  narcotic  and  peripheral  sedative  in  treating  the  mor- 
phine and  alcoholic  habits. 

3.  As  an  anaphrodisiac. 

4.  As  a  mydriatic  and   cycloplegic — one  drop  of  a   i  :  500 
solution  every  fifteen  minutes  for  four  to  six  drops. 

5.  As  a  general  anesthetic  or  as  a  preliminary  to  general  anes- 
thesia. 

Scopolamine-Morphine  or  Scopolamine-Narcophin  Anes- 
thesia.— The  combination  of  scopolamine  hydrobromide  with 
morphine  sulphate  or  narcophin  has  been  employed  in  surgery  as 


4IO  PHARMACOLOGY   AND   THERAPEUTICS 

a  preliminary  to  general  anesthesia  and  as  the  anesthetic  itself, 
and  in  obstetrics. 

As  a  preliminary  to  general  anesthesia,  a  dose  of  scopolamine 
hydrobromide,  about  y^y  grain  (0.00045  gm.)  with  morphine 
sulphate,  i  to  ^  grain  (0.015-0.03  gm.),  given  hypodermatically 
half  an  hour  before  the  general  anesthetic,  is  favored  by  a  number, 
especially  in  operations  upon  nervous  people,  because  it  promotes 
a  tranquil,  drowsy  state  of  mind,  lessens  the  amount  of  general 
anesthetic  required,  diminishes  the  throat  and  bronchial  secre- 
tions during  the  anesthesia,  and  favors  postoperative  sleep  and 
freedom  from  pain. 

As  a  general  anesthetic  about  -,^  grain  (0.0003  gm.)  of  sco- 
polamine hydrobromide  and  £  grain  (0.008  gm.)  of  morphine  sul- 
phate or  narcophin  are  injected  two  and  one-half  hours,  one  and 
one-half  hours,  and  one-half  hour  before  the  operation.  It  is 
sometimes  surprisingly  successful,  but  a  great  many  consider 
it  inefficient  and  dangerous.  In  1988  cases  gathered  from  the 
literature  by  Wood  the  anesthesia  proved  unsatisfactory  in  69 
per  cent.,  and  in  a  number  of  cases  had  to  be  supplemented  by 
ether.  In  addition,  though  the  cases  selected  for  this  method 
were  as  a  rule  the  less  serious  ones,  there  were  9  deaths  which 
could  beyond  reasonable  doubt  be  attributed  to  the  drug,  that 
is  i  in  221,  a  high  rate  of  mortality  for  an  anesthetic. 

In  obstetrics  it  has  come  to  be  known  as  twilight  sleep,  though 
Shears  calls  it  "morphine-stupor."  The  method  elaborated  by 
Kroenig  and  Gauss  at  their  Freiburg  clinic  is  as  follows :  When  the 
patient  is  in  active  labor  with  pains  every  four  or  five  minutes  and 
the  cervix  admitting  two  to  three  fingers,  she  is  isolated  in  a 
darkened  quiet  room  and  given  a  hypodermic  of  scopolamine 
hydrobromide,  gr.  y^  (0.00045  gm-)  with  narcophin,  grain  | 
(0.03  gm).  An  hour  later  TJ-7  grain  (0.00015  gm.)  of  scopolamine 
hydrobromide  is  given.  After  another  half-hour  memory  tests 
are  instituted;  if  she  does  not  remember  the  number  of  injections 
given,  or  when  last  examined,  or  objects  seen  within  half  an 
hour,  she  is  in  the  required  state  of  seminarcosis.  If  there  is 
still  no  amnesia,  a  further  dose  of  ^^  grain  (0.00015  gm.)  of 
scopolamine  hydrobromide  is  given,  and  this  is  repeated  every 
hour  or  hour  and  a  half  as  needed  to  maintain  amnesia.  Ordinar- 
ily only  one  dose  of  narcophin  is  given,  but  if  the  patient  is  very 
restless,  \  grain  (0.015  gm.)  more  is  injected.  The  whole  object 
of  the  treatment  is  to  abolish  retention  in  the  memory  of  the 
pains  and  distresses  of  the  labor.  On  this  account  Kroenig 
recommends  ethyl-chloride  inhalation  as  the  head  is  expelled, 
and  the  immediate  removal  of  the  child  from  the  room  lest  the 
crv  arouse  the  mother. 


ANHIDROTICS  411 

In  spite  of  extensive  magazine  and  newspaper  exploitation, 
the  method  has  been  largely  abolished.  It  causes  a  prolonga- 
tion of  the  second  stage  of  labor,  lessens  the  strength  of  the  uterine 
contractions  and  so  favors  post-partum  hemorrhage,  is  the  cause 
of  an  abnormal  number  of  asphyxiated  babies,  and  is  uncertain 
in  result  (in  500  cases  Zwiefel  reports  successful  amnesia  in  only 
31  per  cent.).  Furthermore  the  mother  requires  constant  watch- 
ing, for  there  may  be  nausea,  vomiting,  headache,  great  mental 
excitement  or  delirium,  or  collapse.  A  few  maternal  deaths  and 
quite  a  number  of  infantile  deaths  are  reported. 

Homatropine  hydrobromide  (U.  S.  P.)  is  the  hydrobromide  of 
an  artificial  alkaloid  allied  to  atropine.  It  is  made  by  the  condensa- 
tion of  tropine  and  oxytoluic  or  mandelic  acid.  It  is  soluble  in  5.7 
parts  of  water,  and  is  used  solely  for  its  ocular  effects,  one  drop 
of  the  i  per  cent,  solution  being  dropped  in  the  eye  every  fifteen 
minutes  for  4  to  6  drops.  Dilatation  of  the  pupil  comes  on 
quickly,  reaches  its  maximum  in  one  to  two  hours,  and  is  followed 
very  soon  by  paralysis  of  accommodation.  The  restoration  of  the 
accommodation  to  normal  occurs  in  twenty-four  hours,  and  full 
restoration  of  the  pupil  in  forty-eight  to  seventy-two  hours — 
i.  e.,  much  more  quickly  than  after  atropine. 

Homatropine  is,  therefore,  preferred  to  atropine  for  fitting 
glasses  and  in  ophthalmoscopic  examinations;  while  atropine  is 
preferred  where  continuous  mydriasis  is  desired,  as  in  inflamma- 
tory conditions  of  the  eyeball.  Physostigmine  will  hasten  the 
restoration  of  the  eye,  and  it  is  the  consensus  of  opinion  among 
ophthalmologists  that,  to  avoid  a  possible  glaucoma,  homatro- 
pine  should  always  be  followed  by  physostigmine. 

ANHIDROTICS 

An  anhidrotic  (anhydrotic)  is  a  remedy  which  tends  to  reduce 
sweating.  For  local  sweating,  as  of  the  hands  and  feet,  alcohol, 
eau  de  cologne,  spirit  of  camphor,  a  25  per  cent,  solution  of 
aluminium  chloride,  and  belladonna  liniment  are  favorites. 
For  odorous  perspiration  of  the  feet  alcohol  may  be  used  as  a 
wash,  and  a  mixture  of  boric  and  salicylic  acids  placed  in  the 
shoes  or  stockings. 

The  chief  use  of  a  general  anhidrotic  is  in  the  night-sweats  of 
tuberculosis.  (See  discussion  under  Antipyretics  and  Dia- 
phoretics.) The  anhidrotic  measure  may  be  a  hot  bath  on  going 
to  bed,  or  a  body  sponge  with  alcohol,  vinegar  (or  acetic  acid), 
or  a  solution  of  alum;  or  it  may  be  a  drug  taken  internally. 
Atropine  is  our  most  powerful  anhidrotic.  It  has  the  advantage 
of  stimulating  respiration,  but  it  has  the  undesirable  effects  of 


412  PHARMACOLOGY  AND  THERAPEUTICS 

drying  the  throat  and  increasing  the  cough,  and  may  even  dilate 
the  pupil.  In  very  extensive  tests  the  author  found  that  for 
internal  administration  in  tuberculosis  the  best  general  anhidrotic 
is  agaricin.  Strychnine  is  also  of  value.  Ergot,  which  has  been 
highly  recommended,  seemed  to  have  no  effect  at  all.  Calcium 
chloride  is  sometimes  effective. 

Agaricin  is  an  unofficial  extract  obtained  from  the  fungus, 
Polyporus  albus,  which  grows  on  the  European  larch.  It  is 
really  an  impure  form  of  the  crystalline  principle,  agaric  acid. 
Its  dose  is  -^  grain  (0.006  gm.).  In  this  dose  it  strongly  de- 
presses the  ends  of  the  secretory  nerves  of  the  sweat-glands,  has 
no  undesirable  side-effects,  and  is  strongly  anhidrotic;  but  its 
effects  are  not  lasting,  so  it  must  be  given  within  four  or  five 
hours  of  the  expected  sweat.  If  the  sweat  comes  on  toward 
morning,  the  dose  may  have  to  be  repeated  once  in  the  night. 
In  larger  doses  it  sometimes  induces  nausea,  vomiting,  diarrhea, 
and  perhaps  dryness  of  the  throat,  but  it  does  not  dilate  the 
pupil.  Doses  large  enough  to  produce  nausea  do  not  give  the 
anhidrotic  action. 

Camphoric  acid,  C8Hi4(COOH)2,  is  an  oxidation  product  of 
camphor.  It  is  soluble  in  alcohol  and  the  fixed  oils,  and  slightly 
in  water.  Its  dose  is  15  grains  (i  gm.),  given  in  cachet  or  powder. 
Its  taste  is  disagreeable,  and  its  systemic  action  is  mildly  that 
of  camphor;  but  practically  its  sole  use  in  medicine  depends  upon 
its  anhidrotic  property.  Roth  (1911)  found  it  to  be  without 
any  direct  effect  upon  the  sweat-glands,  and  was  disposed  to 
attribute  its  action  in  the  night-sweats  of  tuberculosis  to  stimu- 
lation of  the  respiratory  center. 

COCAINE 

Cocaine  is  an  alkaloid  obtained  from  the  leaves  of  Erythroxy- 
lon  coca,  or  of  Erythroxylon  truxillcnse  (Earn.  Erythroxylaced). 
The  coca  shrub  is  extensively  cultivated  at  an  elevation  of  3500  to 
6000  feet  in  the  mountains  of  Peru,  Bolivia,  and  Ecuador,  and 
to  some  extent  also  in  Mexico  and  the  East  and  West  Indies. 
It  has  been  estimated  that  100,000,000  pounds  of  the  leaves  are 
used  annually  in  South  America.  They  yield  cocaine  and  several 
other  alkaloids,  all  compounds  of  ecgonine.  Cocaine  is  the 
methyl-benzoic  acid  compound;  cinnamyl-cocaine  is  the  cin- 
namic  acid  compound,  and  truxilline  is  the  truxillic  acid  com- 
pound. 

Coca  itself  is  used  to  some  extent  in  the  form  of  a  wine,  but 
the  only  pharmacopccial  representatives  are  cocaine,  soluble 
in  oil,  and  cocaine  hydrochloride,  soluble  in  0.4  part  of  water  and 


COCAINE 


413 


3.2  of  alcohol,  but  insoluble  in  oil.  This  alkaloid al  salt  is  decom- 
posed at  a  temperature  of  about  98°  C.,  so  its  aqueous  solution 
cannot  be  sterilized  by  boiling.  Its  solutions  are  not  antiseptic, 
and  frequently  show  a  growth  of  mold.  This  mold  development 
may  be  retarded  by  the  addition  of  boric  acid.  The  following 
formulae  show  the  close  relation  between  atropine,  cocaine,  and 
tropacocaine. 


Tropine 
CH2 CH CH2 


Atropine 

CH2 CH CH2 

/  I 

NCHs 


Ecgonine 

:H2  —  CH  —  CH.COOH   c 

NCH,        CHOH 
\               1 

Cocaine 
•>fr            ptr 

^n2          v_,n 

/ 
NCH3 

\ 

CH2 CH CH, 


CH2 


-CH- 


CH.COOCH3 


-CH2 


Tropacocaine 
CH2 CH CH2 

/  I 

NCH3       CH.O.CO.C6H6 

\  I 

CH2 CH CH2 

Pharmacology. — Cocaine  is  of  great  importance  pharmaco- 
logically, for  it  is  very  extensively  employed  as  a  local  anesthetic, 
has  marked  poisonous  properties,  and  is  one  of  the  "vicious 
habit"  drugs. 

Local. — Cocaine  is  a  general  protoplasmic  poison,  capable 
of  irritating  and  destroying  cells,  or  of  stopping  .the  motions  of 
leukocytes,  amebae,  and  ciliated  cells.  Solutions  above  5  per 
cent,  in  strength  injected  hypodermatically  may  result  in  death 
of  tissue,  which  shows  either  as  a  necrotic  area  of  the  skin  or  as 
a  sterile  abscess;  the  application  to  the  eye  may,  for  the  same 
reason,  result  in  cloudiness  or  ulceration  of  the  cornea.  This 
effect  is  not  usually  seen,  but  it  occurs  often  enough  to  be  of 
importance. 

From  application  to  mucous  membranes  or  injection  beneath 
the  skin  there  promptly  follows  complete  abolition  of  pain, 
from  depression  of  the  ends  of  the  sensory  nerves  or  their  ad- 
jacent nerve-fibrils.  In  addition,  there  is  local  constriction 
of  the  arterioles  from  stimulation  of  both  muscle  and  vasocon- 
strictor nerve-endings.  The  constriction  of  the  vessels  is  not  so 
great  as  that  from  epinephrine.  The  anesthesia  and  constriction 
come  on  in  one  to  four  minutes  and  last  from  fifteen  minutes  to 
one  hour. 


414  PHARMACOLOGY   AND   THERAPEUTICS 

The  drug  cannot  penetrate  the  unbroken  skin.  The  author 
kept  a  finger  for  fifteen  minutes  in  a  20  per  cent,  aqueous  solution 
of  cocaine  hydrochloride,  and  it  showed  neither  anesthesia  nor 
blanching,  though  one  drop  of  the  liquid  on  the  tongue  was 
quickly  followed  by  loss  of  sensation.  But  cocaine  is  readily 
absorbed  through  mucous  membranes  or  the  moist  parts  of  the 
vulva.  After  the  injection  or  application  there  may  be  a  momen- 
tary irritation,  but  very  quickly  there  is  complete  loss  of  the 
sense  of  pain,  with  shrinkage  and  paling  of  the  part  from  compara- 
tive bloodlessness.  Any  mucous  membrane  to  which  the  drug 
can  be  directly  applied  becomes  shrunken  and  anesthetic  in  this 
way,  e.  g.,  membranes  of  the  nose,  throat,  mouth,  esophagus, 
stomach,  rectum,  vagina,  urethra,  bladder,  and  conjunctiva. 
In  the  hypodermatic  use  the  drug  is  injected  just  beneath  the 
epidermis,  and  its  action  is  prolonged  and  intensified  by  the 
addition  of  epinephrine.  This  further  constricts  the  vessels  and 
prevents  the  too  ready  removal  of  the  cocaine  by  the  circulation. 
For  the  same  reason  it  tends  to  make  the  skin  incision  bloodless. 
In  a  finger  or  toe  prolonging  of  the  local  action  may  result  from 
the  application  of  a  tourniquet  or  band  to  impede  the  venous 
return  flow. 

In  the  anesthesia,  though  the  sense  of  pain  is  promptly  lost, 
the  sense  of  touch  is  not  so  readily  abolished,  and  the  tempera- 
ture is  scarcely  affected,  if  at  all;  hence  the  touch  of  an  instru- 
ment or  the  heat  of  a  cautery  may  be  felt,  though  pain  is  absent. 
The  drug  at  first  tastes  bitter,  but  the  taste  for  bitter  soon  be- 
comes completely  abolished,  while  that  for  sweet  and  sour  merely 
becomes  dulled,  and  taste  for  salt  is  not  affected.  If  applied  in 
the  nose,  the  sense  of  smell  is  abolished. 

It  has  been  found  that  anesthesia  is  produced  if  the  drug  is 
applied  to  any  part  of  the  nerve,  from  the  nerve-ending  to  the 
posterior  root;  so  anesthesia  in  therapeutics  may  be  obtained— 

(a)  by  the  application  of  the  solution  to  a  mucous  membrane; 

(b)  by  its  injection  beneath  the  mucous  membrane  or  skin;  (c) 
by  its  injection  into  the  nerve;  or  (d}  by  its  injection  into  the 
spinal  canal,  so  that  it  may  reach  the  posterior  roots.     This  last 
method  is  known  as  "spinal  analgesia"  or  "spinal  anesthesia." 
Cocaine  has  not  the  marked  selective  action  of  atropine,  but  from 
10  c.c.  of  i  to  3  per  cent,  solution  Ritter  (1909)  obtained  in  dogs 
a  general  anesthesia  lasting  from  fifteen  to  thirty  minutes.     The 
dogs  were  fully  awake,  but  quiet  and  indifferent  and  insensitive 
to  pain.     Meltzer,  Kast,  and  Meyer  obtained  similar  effects  in 
animals. 

The  drug  affects  sensory  nerves  very  readily,  but  not  so 
readily  the  motor  nerves.  If  both  sciatics  of  a  frog  be  exposed 


COCAINE  415 

high  up  in  the  thigh,  and  a  little  cocaine  injected  into  the  sub- 
stance of  one  of  them,  an  electric  stimulus  to  the  nerve  on  the 
uncocainized  side  (or  above  the  cocainized  area  on  the  other  side) 
produces  the  usual  reflex  results,  notably  contraction  of  the 
splanchnic  arteries.  But  no  such  results  follow  the  electric 
stimulation  of  the  cocainized  nerve  below  the  area  of  injection. 
Evidently,  then,  the  afferent  impulses  on  the  cocainized  side  are 
blocked  and  do  not  pass  the  cocaine. 

But  the  electric  stimulation  of  the  sciatic  above  the  cocain- 
ized area  produces  the  usual  muscular  contraction  in  the  leg  be- 
low, so  that  motor  impulses  are  not  Hocked  by  the  cocaine.  There 
is,  perhaps,  a  slight  hindrance  to  the  passage  of  motor  impulses, 
as  mentioned  by  Crile. 

Spinal  Analgesia. — To  obtain  spinal  analgesia,  \  or  |  grain 
(0.015-0.03  gm.)  of  cocaine  hydrochloride  in  aqueous  solution  is 
injected  into  the  spinal  canal,  the  needle  being  inserted  between 
the  third  and  fourth  lumbar  vertebrae  into  the  region  of  the  cauda 
equina.  The  toes  and  perineum  become  anesthetic  in  about 
three  or  four  minutes,  and  the  anesthesia  rapidly  ascends  until 
it  reaches  about  to  the  umbilicus,  the  whole  of  the  body  below 
this  point  being  anesthetized.  There  is  little  or  no  muscular 
relaxation;  the  sense  of  touch  may  not  be  altogether  abolished, 
and  the  sensations  of  heat  and  cold  are  unchanged.  (See  also 
Shock  and  Collapse.) 

Jonnesco  has  recently  made  the  injections  higher  up  in  the 
spinal  cord,  using  a  mixture  of  stovaine  and  strychnine.  He 
reports  using  the  method  without  a  fatality  in  1005  patients, 
ranging  from  one  month  to  eighty-two  years.  Transient  arrest 
of  respiration  occurred  seven  times.  He  reports  1958  cases  of 
its  use  by  others  with  safety.  But  this  method  has  not  met 
with  favor  in  this  country,  and  after  many  trials  has  been 
abandoned  as  unsafe.  Gray  and  Parsons  and  Smith  and  Porter 
obtained  a  pronounced  fall  in  blood-pressure  from  the  high  injec- 
tions and  not  from  the  low.  Experimentally,  it  has  been  shown 
that  cocaine  injected  into  the  spinal  canal  can  absolutely  block 
the  strychnine  convulsions  of  that  region,  but  the  strychnine  con- 
vulsions come  on  in  the  muscles  supplied  by  the  uncocainized 
parts  of  the  cord.  Gabbett  (1910)  reports  a  death  from  the 
injection  of  novocaine,  i|  grains  (0.6  gm.),  and  strychnine 
hydrochloride,  •£•%  grain  (o.ooi  gm.).  The  convulsions  affected 
the  arms,  but  not  the  lags. 

The  Eye. — If  a  drop  of  2  or  4  per  cent,  aqueous  solution  of 
cocaine  hydrochloride  is  dropped  into  the  eye,  the  immediate 
effect  is  marked  irritation,  with  reflex  contraction  of  the  pupil. 
But  this  is  followed  quickly  by  anesthesia  of  cornea  and  conjunc- 


416  PHARMACOLOGY   AND   THERAPEUTICS 

tiva,  with  blanching,  retraction  of  the  eyelids,  and  absence  of  the 
winking  reflex  hi  response  to  an  irritant.  A  few  minutes  later 
the  pupil  becomes  dilated,  and  remains  so  for  one  or  two  hours. 
The  pupil  still  reacts  to  light,  though  only  partially,  and  there  is 
neither  paralysis  of  accommodation  nor  decrease  in  intra-ocular 
tension,  so  the  effect  on  the  eye  is  different  from  that  produced  by 
atropine.  This  is  further  shown  by  the  fact  that  in  a  fully 
atropinized  eye  cocaine  still  further  dilates  the  pupil,  and  that  in 
a  cocainized  eye  the  pupil  contracts  on  electric  stimulation  of  the 
third  nerve,  either  centrally  or  distally  to  the  ciliary  ganglia. 
These  experiments  show  that  it  does  not  act  on  the  third  nerve. 

The  action  of  the  cocaine  is  evidently  a  peripheral  one.  If 
it  is  injected  into  an  excised  eye,  it  causes  the  same  dilatation  of 
the  pupil.  If  the  superior  cervical  ganglion  (from  which  the 
pupil-dilating  fibers  emanate)  is  removed  from  one  side  of  an 
animal,  and  after  the  wound  has  healed  and  the  nerves  have  had 
time  to  degenerate,  cocaine  is  dropped  in  each  eye,  there  is  a 
dilatation  of  the  pupil  on  the  intact  side,  but  on  the  other  side 
only  slight  dilatation  if  any.  Hence,  though  there  may  be  some 
depression  of  the  circular  muscles,  the  main  action  is  stimulation 
of  either  the  radial  muscle-fibers  or  some  part  of  their  (sym- 
pathetic) nerve-supply. 

Accommodation  is  not  paralyzed,  as  the  ciliary  muscle  is  not 
affected;  so  cocaine  is  not  available  in  fitting  glasses. 

The  intra-ocular  tension  is  not  increased,  and  in  spite  of  the 
dilatation  of  the  pupil,  which  lasts  only  an  hour  or  two,  may  be 
diminished.  This  effect  is  thought  to  be  due  both  to  the  shrink- 
age of  the  vessels  of  the  eyeball  and  to  the  consequent  diminu- 
tion in  secretion. 

If  one  drop  of  a  4  per  cent,  cocaine  solution  is  dropped  in  the 
eye  every  minute  for  five  minutes,  the  pupil  will  be  fairly  dilated 
in  about  five  minutes  more,  and  the  dilatation  will  last  for  from 
one  to  two  hours.  A  danger  is  the  drying  of  the  cornea,  with 
ulceration  or  clouding. 

The  Stomach. — Cocaine  is  locally  anesthetic,  and  will  prevent 
vomiting  from  local  irritants.  It  is  of  interest  that  in  the  Andes 
Mountains  the  natives  chew  coca  leaves,  and  if  they  have  a 
plentiful  supply  of  coca,  can  continue  to  work  for  several  days 
without  food.  They  seem  to  have  no  feeling  of  hunger  so  long 
as  food  is  kept  out  of  their  sight,  but  the  appetite  returns  if  they 
see  or  smell  appetizing  food.  Probably  there  is  diminished 
sensation  in  the  stomach  and  in  the  mouth,  and  consequent 
absence  of  the  effect  on  appetite  of  reflexes  from  these  regions, 
while  the  psychic  elements  in  the  production  of  appetite  (the 
sight  or  smell  of  food)  remain  intact.  The  psychic  stimulation 


COCAINE  417 

is  also  probably  a  factor  in  producing  increased  power  to  work. 
It  is  said  that  100,000,000  pounds  of  the  leaves  are  used  annually 
in  South  America,  the  people  chewing  them  with  the  addition  of  a 
little  chalk  or  lime. 

These  effects  have  not  been  obtained  in  other  localities,  and 
consequently  have  been  attributed  to  some  unexplained  property 
which  is  confined  to  the  fresh  or  freshly  dried  coca  leaves.  But 
Sollmann  thinks  that  these  effects  have  failed  in  northern  regions 
because  the  drug  has  not  been  tried  in  conditions  of  marked 
hunger  and  fatigue.  Miiller  and  also  Schlesinger  found  little 
or  no  abolition  of  hunger  by  cocaine,  though  it  abolished  the 
feeling  of  weakness. 

Disagreeable  central  effects  upon  the  alimentary  tract  which 
not  infrequently  follow  the  absorption  of  cocaine,  as  in  spinal 
anesthesia,  are  nausea,  vomiting,  and  diarrhea.  The  cause  of 
these  is  not  known. 

Systemic  Effects. — The  systemic  effects  are  not  made  use  of 
in  therapeutics,  and  may  be  studied  rather  because  of  their  mani- 
festation in  poisoning. 

Heart. — In  perfusing  the  isolated  heart  the  addition  of  co- 
caine does  not  change  the  rate  or  force  of  the  beat,  therefore 
neither  the  muscle  nor  the  accelerator  endings  nor  the  vagus  end- 
ings are  affected.  But  in  the  intact  mammal,  after  a  moment  of 
slowing  from  slight  vagus  center  stimulation,  the  heart  beats 
faster,  and  as  it  does  not  do  so  when  both  accelerators  are  cut, 
the  effect  must  be  stimulation  of  the  accelerator  center.  The 
vagus  endings  retain  their  sensitiveness,  for  even  late  in  the 
poisoning  stimulation  of  a  vagus  nerve  results  in  slowing. 

After  lethal  doses  the  heart  eventually  becomes  weak  and  slow 
from  direct  muscular  depression  (or  perhaps  vagus  stimulation), 
and  death  may  take  place  from  cardiac  failure.  Occasionally,  an 
unexplained,  almost  instant,  collapse  follows  the  absorption  of 
the  drug,  even  when  it  is  used  locally.  In  the  hearts  of  cold- 
blooded animals,  C.  C.  Lieb  has  repeatedly  obtained  auriculo- 
ventricular  dissociation  (heart-block). 

Arteries. — The  vasoconstrictor  center  is  stimulated  and  blood- 
pressure  rises;  in  severe  poisoning  this  center  is  depressed. 
From  ordinary  amounts  there  is  no  direct  effect  upon  the  arteries, 
such  as  occurs  from  the  local  application,  as  the  drug  is  not  suf- 
ficiently selective  in  its  great  dilution  by  the  blood.  Kuroda 
(1915)  showed  that  perfusion  of  an  organ  resulted  in  dilatation  of 
the  arteries. 

Crile  calls  attention  to  the  important  fact  that  after  an  in- 
travenous injection  of  cocaine  the  splanchnic  arteries  arc  more 
resistant  to  influences  which  usually  cause  their  dilatation,  e.  g., 
27 


41 8  PHARMACOLOGY   AND   THERAPEUTICS 

shock,  handling  the  viscera,  etc.  Hatcher  and  Wilbert  state 
that  an  intravenous  dose  of  cocaine  too  small  to  affect  the 
circulation  will  increase  the  sensitiveness  of  the  vasomotor 
system  to  epinephrine. 

Respiration. — The  respiratory  center  is  strongly  stimulated, 
and  the  respiration  is  increased  both  in  rate  and  in  depth.  Death 
is  usually  due  to  respiratory  failure,  though  it  is  not  so  always. 

Cerebrum. — This  is  stimulated  in  much  the  same  way  as  with 
atropine,  even  the  local  use  of  the  drug  being  followed  by  talka- 
tiveness and  cheerfulness,  and  even  delirium  and  cerebral  con- 
vulsions. But  as  an  intellectual  stimulant  it  seems  to  rank 
higher  than  atropine,  for  the  cocaine  jag  is  characterized  by  in- 
creased intellectual  power  and  self-possession,  in  addition  to 
loquacity.  The  reaction  time  is  shortened,  and  it  is  more  dif- 
ficult to  put  and  keep  an  animal  under  chloroform  or  ether,  i.  e., 
cocaine  antagonizes  narcosis. 

The  motor  areas  of  the  brain  are  stimulated,  and  also  the  re- 
flex centers  of  brain  and  cord,  and  there  is  a  tendency  to  motor 
activity  and  restlessness,  so  that  the  patient  wants  to  walk 
about.  A  dog  will  run  amuck,  usually  in  a  circle,  and  quite  in- 
different to  his  surroundings.  The  ergograph  shows  an  actual 
increase  in  muscular  power.  All  these  things  are  evidences  of 
true  central  stimulation,  exactly  the  opposite  of  the  effect  of 
alcohol  or  morphine. 

After  highly  poisonous  doses  the  stimulation  is  followed  by 
depression,  stupor,  cerebral  (not  spinal)  convulsions,  and  coma. 

Medulla. — The  respiratory,  vasoconstrictor,  and  accelerator 
centers  are  stimulated.  Whether  the  vagus  center  is  stimulated 
to  any  great  extent  or  not  is  a  moot  question.  In  poisoning,  the 
thermogenetic  center  in  the  caudate  nucleus  is  affected,  so  that 
the  temperature  may  rise  several  degrees. 

Muscle. — There  is  no  direct  effect,  but  the  motor  areas  are 
stimulated  so  that  muscular  power  is  increased  and  fatigue  is 
lessened. 

Temperature. — See  under  Medulla.  The  rise  in  temperature 
has  probably  the  same  explanation  as  that  after  atropine. 
The  temperature  does  not  rise  in  chloralized  animals. 

Excretion. — Some  of  it  is  destroyed  in  the  body,  though 
experiments  at  the  University  of  Berlin  (1913)  would  indicate 
that  cocaine  is  in  some  degree  excreted  unchanged  by  the  kidneys. 
The  urine  is  sometimes  increased,  sometimes  diminished,  prob- 
ably through  changes  in  the  kidney  circulation.  The  effect  upon 
it  is  unimportant. 

Untoward  Effects. — Untoward  effects  following  its  use  for 
anesthesia  are: 


COCAINE  419 

(a)  From  protoplasmic  irritation — cloudiness  or  ulceration  of 
the  cornea;  necrotic  area  or  sterile  abscess  at  the  site  of  injection. 

(b)  After    absorption — (i)  Talkativeness,     excitement,    and 
wakefulness.     (2)  A  profound  narcosis  instead  of  excitement. 
(3)  Nausea,  vomiting,  and  diarrhea,  sometimes  distressing.    (4) 
Sudden  collapse  without  warning. 

Acute  Poisoning. — A  number  of  cases  are  reported.  An  over- 
whelming dose  may  cause  prompt  stoppage  of  heart  and  respira- 
tion, or  complete  relaxation  of  the  arteries  with  collapse  (Smith 
and  Porter) .  In  some  cases  there  is  great  susceptibility  and  there 
are  many  reports  of  sudden  collapse  and  death  in  the  physician's 
office  after  the  local  use  in  nose,  throat,  eye,  and  urethra.  Great 
excitement,  collapse,  and  respiratory  failure  have  resulted  from 
2  drops  of  a  4  per  cent,  solution  in  the  eye;  also  conjunctivitis. 
One  of  my  cases  has  twice,  following  cocaine  in  the  eye,  had  a 
dilatation  of  the  arterioles  on  that  side  of  the  face,  so  that  it 
was  flushed  and  hot,  an  effect  which  regularly  follows  sympathetic 
paralysis.  Harris  reports  death  from  very  small  amounts  in  a 
case  \vith  status  lymphaticus. 

In  ordinary  poisoning  the  central  symptoms  resemble  those 
from  atropine.  They  are  often  observed  after  a  cocaine  debauch 
in  a  habitue.  These  symptoms  are  garrulousness,  restlessness, 
motor  activity,  with  incoordination  like  in  a  drunken  man,  ex- 
citement, hallucinations,  and  delusions;  nausea  and  vomiting; 
rapid  heart  with  raised  blood-pressure;  respiration  quick  and 
deep,  or  even  panting;  pupil  dilated;  throat  dry.  There  are 
frequently  great  anxiety  and  fear  that  death  will  take  place,  and 
anginal  pains  about  the  heart.  Magnan's  sign  is  a  subjective 
sensation  as  of  pimples  or  worms  beneath  the  skin  or  of  vermin  on 
the  skin.  Following  the  excitement  there  are  drowsiness,  stupor, 
coma,  collapse,  cerebral  convulsions,  and  death  from  failure  of 
the  heart  or  respiratory  center.  It  may  be  distinguished  from 
atropine  poisoning  by  Magnan's  sign  and  the  reaction  of  the 
pupil  to  light,  and  by  the  fact  that  atropine  checks  sweating, 
and  may  be  found  in  the  concentrated  urine  in  sufficient 
amount  to  dilate  the  pupil  of  a  cat's  eye.  Failure  of  the  heart 
to  react  to  pressure  on  the  vagus  in  the  neck  would  suggest 
atropine. 

Treatment. — Because  of  the  marked  anxiety  it  is  of  great  im- 
portance to  reassure  the  patient.  In  the  excitement  stage  an 
ice-bag  to  the  head  and  whisky  or  large  doses  of  bromides  may 
be  supplied,  or  even  inhalations  of  ether.  In  the  collapse  stage 
the  treatment  is  for  collapse,  especial  attention  being  paid  to  the 
respiratory  center.  C.  C.  Lieb  has  repeatedly  checked  cocaine 
heart-block  in  isolated  turtle  hearts  by  caffeine;  but  caffeine 


42O  PHARMACOLOGY  AND  THERAPEUTICS 

increases  the  poisoning  of  the  central  nervous  system  and  is 
ordinarily  contraindicated. 

Cocaine  Habit. — The  cocaine  habit  is  quite  common,  espe- 
cially among  nurses,  physicians,  and  druggists,  who  have  easy 
access  to  the  drug,  among  prostitutes,  and  among  the  negroes  of 
the  South.  The  drug  is  taken  as  snuff,  or  is  rubbed  into  the  gums, 
swallowed,  or  injected  hypodermatically.  The  habit  may  be 
diagnosed  by  the  nervousness  and  twitching  in  the  absence  of  the 
dose,  by  the  marks  of  a  hypodermatic  needle,  by  ulceration  in  the 
nose,  with  epistaxis,  if  the  snuff  is  taken,  and  by  the  effects  of 
a  "fake"  dose  of  some  other  drug.  Blue  atrophy  of  the  skin  at 
the  site  of  the  injections  has  been  reported  by  Gottheil  (1912). 

When  without  his  usual  dose  the  habitue  feels  irritable,  de- 
pressed, and  restless,  and  cannot  concentrate  his  attention;  on 
getting  the  dose  his  spirits  brighten  and  he  experiences  a  return  of 
his  mental  and  physical  energies.  By  degrees  he  passes  into 
a  state  of  poor  nutrition,  wasting,  and  anemia,  with  loss  of  appe- 
tite, deranged  digestion,  constipation,  and  insomnia.  He  grad- 
ually reaches  a  state  of  mental  and  moral  weakness  without 
self-control,  far  beyond  those  of  the  morphine  or  heroine  habitue, 
is  easily  depressed,  develops  careless  and  debasing  habits,  and 
lacks  the  inclination  to  work.  He  may  develop  various  mental 
and  nervous  symptoms,  such  as  tremor  of  hands  and  lips,  ir- 
regular twitching  of  the  shoulder  and  other  muscles,  queer  sensa- 
tions in  the  skin,  and  hallucinations  and  delusions.  The 
delusions  cause  great  viciousness,  and  perhaps  attempts  to  harm 
others.  Mania  and  chronic  dementia  and  other  forms  of  insanity 
as  results  of  the  habit  are  reported. 

Treatment. — Isolation,  the  rapid  or  even  the  immediate  with- 
drawal of  the  drug,  with  the  substitution  of  atropine  or  hyoscine, 
and  attention  to  nutrition,  digestion,  bowels,  and  sleep. 

Therapeutics. — The  wine  of  cooa  is  employed  to  some  extent 
as  a  tonic  and  appetizer  in  run-down  conditions,  or  in  convales- 
cence from  acute  illnesses.  Since  it  has  the  taste  of  wine  and 
contains  \  grain  or  more  of  cocaine  and  allied  alkaloids  in  each 
ounce,  it  is  not  surprising  that  a  number  of  cases  of  cocaine 
habit  have  resulted  from  its  use.  It  is  not  now  Pharmacopceial. 

Cocaine  hydrochloridc  is  employed  very  extensively  as  an  anes- 
thetic, either  by  application  to  mucous  membranes  in  2  to  10 
per  cent,  solution,  by  hypodermatic  injection  in  0.2  to  4  per  cent, 
solution,  or  by  injection  of  \  grain  (0.03  gm.)  in  solution  into  the 
spinal  canal. 

In  the  nose,  besides  its  use  as  an  anesthetic,  it  is  employed  to 
shrink  the  tissues  so  as  to  favor  the  passage  of  instruments,  to 
increase  the  view,  to  stop  hemorrhage,  or  to  free  the  nasal  passages 


COCAINE  42 1 

and  to  lessen  engorgement  in  rhinitis  and  hay-fever.  It  is 
inferior  to  adrenaline  for  these  purposes.  Many  cases  of  cocaine 
habit  can  be  traced  to  the  use  of  sprays  and  powders  in  hay-fever, 
and  not  a  few  to  the  use  of  proprietary  asthma  cures  and  catarrh 
snuffs. 

In  the  throat  it  may  be  sprayed  over  a  hypersensitive  pharynx 
before  examination  with  a  laryngoscope,  or  to  check  a  distress- 
ing dry  cough,  or  in  tuberculous  laryngitis  to  abolish  pain  and 
permit  the  swallowing  of  food. 

In  affections  of  the  esophagus  (ulcer,  cancer,  esophagitis, 
spasm,  cardiospasm)  cocaine  solution  may  be  swallowed  just  be- 
fore eating,  to  lessen  the  pain  and  spasmodic  contraction  which 
results  from  the  passage  of  food.  A  10  per  cent,  solution  is 
applied  to  the  pharynx  and  larynx  in  direct  laryngoscopy  or 
esophagoscopy  to  prevent  pain  and  shock. 

In  the  stomach  it  is  employed  to  allay  pain,  nausea  and  vom- 
iting; in  the  eye,  as  anesthetic  for  operations  and  the  removal  of 
foreign  bodies,  and  as  a  transient  pupil  dilator  to  facilitate  ex- 
amination of  the  internal  eye;  in  the  urethra,  to  allay  spasm  and 
permit  the  passage  of  instruments;  at  the  anus,  in  ulcer  or  fis- 
sure, to  allow  a  painless  examination  or  painless  defecation;  on 
the  vulva,  to  overcome  intractable  itching,  and  in  the  entrance  to 
the  vagina  in  vaginismus.  In  irritable  rectum  or  anus  it  may  be 
employed  in  ointment  or  suppository  form. 

In  the  external  ear  the  aqueous  solution  is  not  absorbed,  but 
some  anesthesia  may  be  obtained  from  the  pure  alkaloid  dis- 
solved in  aniline  oil.  It  is  reported  that  a  10  per  cent,  solution 
in  ether  will  be  absorbed. 

When  cocaine  is  used  hypodermatically,  it  is  not  injected 
deeply  like  other  drugs  to  hasten  absorption,  but  is  placed  im- 
mediately beneath  the  epidermis.  The  addition  of  epinephrine 
lessens  the  systemic  and  prolongs  the  local  effects,  and  checks 
hemorrhage;  so  in  this  admixture  it  has  recently  come  into  ex- 
tensive use  for  quite  large  operations,  as  amputation  of  a  limb 
or  laparotomy.  It  does  not,  however,  abolish  the  perception  of 
the  patient  or  produce  full  muscular  relaxation.  In  major  opera- 
tions under  general  anesthesia  Crile  and  others  are  attempting 
to  lessen  shock  by  cocainizing  the  operative  area  in  advance  of 
cutting.  Allen  Starr  uses  cocaine  hypodermatically  as  a  diag- 
nostic agent  in  painful  tic,  the  drug  being  injected  at  the  site  of 
that  branch  of  the  fifth  nerve  which  supplies  the  painful  area. 
If  the  pain  disappears,  the  lesion  is  peripheral;  if  not,  it  is  central. 

Spinal  analgesia  with  cocaine  or  one  of  its  relatives,  es- 
pecially novocaine  and  stovaine,  may  be  employed  for  opera- 
tions about  the  perineum  and  lower  extremities  when  a  general 


422  PHARMACOLOGY  AND  THERAPEUTICS 

anesthetic  is  contraindicated,  as  in  severe  diabetes  and  severe 
nephritis.  It  has  also  been  used  to  a  slight  extent  in  obstetrics. 
A  very  important  use  of  it  is  to  prevent  shock  in  severe  traumatism 
of  the  lower  extremities.  Its  value  for  operations  is  limited 
for  the  following  reasons:  (i)  The  extent  of  the  anesthesia  is 
beyond  the  control  of  the  anesthetist,  in  some  cases  the  whole 
body,  even  the  head  and  face,  being  affected.  (2)  There  is 
frequently  vomiting  and  diarrhea  and  excitement,  effects  which 
may  persist  for  hours.  (3)  The  patient  remains  conscious,  and 
is  made  keenly  alert  by  the  drug.  (4)  There  is  little  or  no  mus- 
cular relaxation.  (5)  Cocaine  collapse  sometimes  occurs.  A 
number  of  deaths  are  reported. 

Systemically,  cocaine  is  not  ordinarily  employed  at  all,  but, 
if  other  remedies  are  not  at  hand,  it  may  be  used  as  a  central 
stimulant  in  collapse  from  narcotic  drugs. 

Intravenous  Injection  of  Cocaine. — A  method  of  producing 
local  anesthesia  by  injecting  cocaine  into  the  veins  has  been  more 
or  less  used  (Bier's  vein  anesthesia),  a  tourniquet  above  and  be- 
low the  area  to  be  anesthetized  preventing  the  loss  of  cocaine  and 
causing  the  localized  action.  A  danger  is  clotting  in  the  vein. 

Ritter's  (1909)  experiments  with  dogs,  in  which  he  produced 
general  anesthesia  by  an  intravenous  of  a  i  to  5  per  cent,  solu- 
tion, and  Meyer's  similar  results  with  cats  have  not  been  followed 
by  any  extensive  use  in  man.  Harrison  (1911)  reports  the  effects 
on  himself  of  5  grains  (0.3  gm.)  of  cocaine  hydrochloride  in  2 
per  cent,  solution  introduced  intravenously.  Cerebration  was 
normal  except  for  a  restless  inability  to  keep  the  mind  long  on 
one  subject.  Mo.tor  power  was  unimpaired.  There  were  dizzi- 
ness and  palpitation.  There  was  marked  analgesia  everywhere, 
though  slight  twinges  of  pain  were  felt  on  making  a  f -inch  incision 
through  the  skin.  Two  hours  later  there  was  still  a  slight  im- 
pairment of  feeling.  The  experimenter  says  that  the  results 
are  not  good  enough  to  justify  this  use  of  cocaine. 

COCAINE  SUBSTITUTES 

The  drawbacks  in  the  use  of  cocaine  are: 

1.  Its  general  poisonous  action. 

2.  The  frequency  of  undesirable  idiosyncrasy  to  it. 

3.  Its  decomposition  at  boiling  temperature,  which  prevents 
effective  sterilization. 

4.  Its  poor  keeping  qualities  in  solution. 

5.  Its  tendency  to  vicious  habit  formation. 

Because  of  those  alleged  drawbacks  to  the  use  of  cocaine,  a 
number  of  other  local  anesthetics  have  been  brought  forward  as 


COCAINE    SUBSTITUTES  423 

cocaine  substitutes.  Of  these  the  following  are  closely  related 
chemically,  and  are  employed  in  the  same  strength  as  cocaine: 

Eucaine,  beta-eucaine  chloride  or  lactate,  trimethyl-benzoxy- 
piperidine,  which  is  irritant  locally,  but  may  be  boiled  without 
harm,  does  not  constrict  the  arterioles,  and  has  very  slight  effect 
upon  the  pupil  and  accommodation.  The  chloride  is  soluble  in 
30  parts  of  water,  and  the  lactate  in  20  parts. 

Stovaine,  di-methyl-amino-benzoyl  pentanol  chloride,  which 
is  soluble  in  its  own  weight  of  water,  is  more  irritant  locally,  di- 
lates the  arterioles  on  local  application,  and  in  spinal  analgesia 
induces  muscular  relaxation.  It  is  too  irritant  for  use  in  the  eye, 
and  has  shown  a  greater  tendency  than  cocaine  to  produce  local 
gangrene. 

Alypine,  benzoyl-tetramethyl-diamino-ethyl-isopropylic  alco- 
hol chloride,  readily  soluble  in  water.  Its  solutions  will  not  stand 
boiling.  It  dilates  the  arterioles,  and  has  no  effect  on  either 
pupil  or  intra-ocular  tension. 

Novocaine,  para-amino-benzoyl-diethyl-amino-ethanol  chlo- 
ride, soluble  in  its  own  weight  of  warter,  not  decomposed 
by  boiling,  and  without  effect  upon  the  arterioles.  Schley  found 
that  large  doses  administered  to  guinea-pigs  produced  practically 
the  same  poisonous  symptoms  as  cocaine,  but  it  required  about 
six  times  as  much  of  the  novocaine.  As  it  is  not  absorbed  readily 
by  mucous  membranes  or  the  eye,  it  must  be  used  hypodermat- 
ically.  To  prevent  shock,  Crile  uses  a  solution  of  i  :  400  to  anes- 
thetize the  field  of  operation  in  advance  of  cutting. 

Hatcher  and  Eggleston  find  the  symptoms  less  persistent 
than  those  from  cocaine;  also  that  slow  continuous  intravenous 
injections  of  large  amounts  fail  to  produce  lasting  effects.  Toxic 
amounts  quickly  administered  cause  immediate  stoppage  of 
heart  and  respiration. 

Tropacocaine,  the  benzoyl  ester  of  pseudo-tropine  chloride, 
is  more  irritant  locally,  and  does  not  dilate  the  pupil  or  affect 
the  arterioles.  Its  solutions  can  be  boiled. 

These  drugs  are  all  chemically  related  to  cocaine.  They  are 
found  to  be  less  irritating  to  the  tissues  and  less  destructive  if 
dissolved  in  normal  saline  rather  than  pure  water.  They  are 
all  prompt  in  producing  anesthesia,  and  their  effects  last  only 
from  fifteen  minutes  to  half  an  hour;  but  they  all  maintain  anes- 
thesia for  a  much  longer  period  if  used  with  a  small  amount  of 
epinephrine,  the  anesthesia  being  a  little  slower  in  coming  on. 
The  epinephrine  acts  by  constricting  the  arterioles  so  that  the 
drug  is  not  carried  away  so  rapidly  by  the  blood-stream;  a 
further  advantage  is  that,  by  the  blanched  area,  it  shows  exactly 
where  the  drug  has  been  injected. 


424  PHARMACOLOGY  AND   THERAPEUTICS 

SOME   OTHER  LOCAL  ANESTHETICS  NOT  USED   HYPODERMAT- 

ICALLY 

Orthoform,  methyl-para-amido-meta-oxybenzoic  ester,  is  ap- 
plied as  a  powder  to  painful  ulcers,  or  in  ointment  form  to  pro- 
jecting hemorrhoids  or  to  the  vulva  in  pruritus;  or  is  used  in 
suppositories  in  anal  fissure  or  ulcer,  or  in  the  form  of  lozenges  to 
be  dissolved  in  the  mouth  to  overcome  dry  cough,  or  in  tubercu- 
lous laryngitis  to  permit  swallowing.  It  may  be  taken  inter- 
nally for  ulcer  of  the  stomach.  Dose,  5  grains  (0.3  gm.)  in 
suppository,  lozenge,  capsule,  or  powder.  A  5  or  10  per  cent, 
ointment  is  also  employed.  The  author  has  seen  a  spreading  der- 
matitis of  the  fingers  and  hands  after  the  use  of  an  orthoform 
ointment.  It  occurred  twice  in  the  same  person  and  was  doubt- 
less due  to  idiosyncrasy. 

Anesthesin,  the  ethyl  ester  of  para-amido-benzoic  acid,  has 
the  same  uses  and  dosage  as  orthoform.  It  is  slightly  soluble  in 
water,  and  more  readily  so  in  alcohol  and  the  oils. 

Propaesin,  para-amido-benzoic-acid-propyl  ester  is  a  crystal- 
line powder,  slightly  soluble  in  water  and  moderately  so  in  al- 
cohol. It  is  used  in  the  same  way  as  the  last  named,  in  doses  of 
5  grains  (0.3  gm.)  or  in  10  per  cent,  ointment.  Dipropcesin  is 
a  combination  of  one  molecule  of  urea  with  two  of  propaesin. 
It  is  anesthetic  in  an  alkaline  medium. 

Chloretone,  chlorbutanol,  is  sometimes  employed  in  the  same 
way  (see  under  Hypnotics),  in  powder,  tablets,  spray,  etc.,  as  a 
local  anesthetic. 

Holocaine,  para-diethoxy-ethenyl-diphenyl-amidin  chloride, 
is  very  soluble  in  water,  but  more  irritant  and  more  toxic  than 
cocaine.  In  forty-five  seconds  a  i  per  cent,  solution  produces 
an  anesthesia  of  the  eye  which  lasts  ten  or  fifteen  minutes,  with- 
out any  effect  on  pupil,  accommodation,  intra-ocular  tension, 
or  the  arterioles. 

Dionine,  di-ethyl  morphine  chloride,  is  soluble  in  7  parts  of 
water,  and  is  used  in  5  per  cent,  solution  to  dilate  the  pupil,  to 
lessen  intra-ocular  tension,  and  to  abolish  pain  in  the  eye. 
Snycler  prefers  it  to  eserine  in  glaucoma.  At  first  it  causes  great 
irritation  and  even  chemosis,  but  this  soon  disappears.  Its  sys- 
temic effect  is  similar  to  that  of  codeine.  (See  Morphine.) 

Yohimbine  is  an  alkaloid  yielded  by  a  tree  of  the  Apocynacece 
of  German  West  Africa.  Its  solutions  decompose  on  boiling  and 
deteriorate  on  keeping.  It  is  less  anesthetic  than  cocaine  and 
dilates  the  pupil,  but  it  so  strongly  dilates  the  vessels  that  to 
prevent  hyperemia  a  2  per  cent,  solution  requires  to  be  mixed 
with  an  equal  quantity  of  epinephrine  solution. 


OTHER  ANESTHETICS  NOT  USED  HYPODERMATICALLY   425 

Taken  by  mouth,  yohimbine  is  said  to  cause  a  dilatation  of 
the  cutaneous  vessels,  to  stimulate  the  lower  part  of  the  spinal 
cord,  to  increase  sexuality,  and  to  induce  erections  of  the  penis 
which  may  or  may  not  be  accompanied  by  sexual  desire.  Dose, 
|  grain  (0.008  gm.),  or  in  2  per  cent,  solution  hypodermatically 
8  minims  (0.5  c.c.).  A  number  of  veterinary  writers  have  re- 
ported aphrodisiac  effects  in  cows,  pigs,  and  horses.  Vasotonin, 
a  preparation  of  yohimbin  and  urethane  designed  to  lower  arte- 
rial pressure,  was  found  to  have  the  opposite  effect  (Lawrence). 

Schleich's  infiltration  anesthesia  was  famous  at  one  time. 
He  used  solutions  of  the  hydrochlorides  of  morphine  and  cocaine 
in  three  different  strengths  in  0.2  per  cent,  solution  of  sodium 
chloride.  The  strongest  of  his  solutions  contained  0.2  per  cent,  of 
cocaine  and  0.025  per  cent,  of  morphine. 

Other  local  anesthetics  are  the  ethyl  chloride  spray,  which 
freezes  the  part,  and  is  only  momentary  in  its  effects,  and  phe- 
nol, a  5  per  cent,  solution  of  which,  kept  in  contact  with  the  part, 
will  slowly  numb  and  anesthetize. 

Eriodictyon  (yerba  santa)  is  an  astringent,  resinous,  bitter 
drug,  of  which  the  fluidextract  is  official;  dose,  30  minims  (2  c.c.). 
It  possesses  the  peculiar  local  action  on  the  taste-buds  of  abolish- 
ing the  taste  for  bitter,  though  not  that  for  sweet,  salt,  or 
sour.  If  the  mouth  is  rinsed  with  a  little  of  the  fluidextract  di- 
luted with  water,  a  dose  of  quinine  or  strychnine  taken  three  or 
four  minutes  later  gives  scarcely  any  bitter  taste.  It  is  sometimes 
made  into  a  syrup  and  used  as  a  vehicle  for  the  administration 
of  quinine  to  children;  but  in  such  admixture  it  has  no  time  to 
act  on  the  taste-buds,  and  really  lessens  the  bitterness  of  the 
quinine  salt  by  changing  it  to  the  tannate,  an  almost  insoluble 
and  therefore  almost  tasteless  salt. 


Intravenous  Local  Anesthesia. — This  method,  introduced  by 
Bier,  gives  complete  anesthesia  of  a  limb.  The  blood  is  squeezed 
out  of  the  veins  between  two  Esmarch  bandages,  and  a  0.5  per 
cent,  novocaine  solution  injected  into  a  vein.  The  solution 
reaches  all  parts  of  the  segment,  and  produces  complete  anes- 
thesia of  the  segment  in  five  minutes,  so  that  even  an  amputation 
may  be  performed  without  pain.  In  an  adult  50  to  100  c.c.  of 
the  solution  are  required  for  the  arm,  and  somewhat  more  for 
the  leg. 

Quinine  and  urea  hydrochloride  has  come  into  extensive  use 
as  a  local  anesthetic.  It  is  mostly  used  hypodermatically  and  is 
described  under  "Quinine." 


426  PHARMACOLOGY  AND  THERAPEUTICS 

SOME  PERIPHERAL  DEPRESSANTS  NOT  OF  GREAT 
MEDICINAL  IMPORTANCE 

1.  HYDROCYANIC  ACID  AND  CYANIDES 

Preparations. — Diluted  hydrocyanic  acid,  HCN,  a  2  per  cent, 
solution;  dose,  i  minim  (0.06  c.c.).  It  rapidly  deteriorates  on 
keeping.  Undiluted  hydrocyanic  (prussic)  acid  is  not  employed 
in  medicine. 

Polassium  cyanide,  KCN;  dose,  \  grain  (o.oi  gm.). 

In  addition,  hydrocyanic  acid  is  present  in  preparations  of 
wild-cherry  bark  (Prunus  virginiana),  the  oil  of  bitter  almond 
(Amygdala  amara),  and  cherry-laurel  leaves  (Laurocerasus).  In 
these  it  does  not  occur  in  the  crude  drugs,  but  is  developed  in  the 
presence  of  water  by  the  action  of  the  ferment  emulsin  on  the 
glucoside  amygdalin,  both  of  which  are  present.  (For  the  re- 
action, see  Part  I,  Glucosides.)  The  official  oil  of  bitter  almond 
contains  2  to  4  per  cent,  hydrocyanic  acid  and  85  per  cent, 
benzaldehyde;  dose,  i  minim  (0.06  c.c.).  The  preparations  of 
these  are: 

Infusion  of  wild  cherry,  4  per  cent.;  dose,  2  ounces  (60  c.c.). 

Syrup  of  wild  cherry,  15  per  cent.;  dose,  i  dram  (4  c.c.). 

Fluidextract  of  wild  cherry;  dose,  30  minims  (2  c.c.). 

Bitter  almond  water  (aqua  amygdalae  amarae),  o.i  per  cent.; 
dose,  i  dram  (4  c.c.). 

Spirit  of  bitter  almond,  i  per  cent.,  3  minims  (0.2  c.c.). 

Action. — Cyanides  are  general  protoplasmic  poisons,  highly 
toxic  to  all  living  things,  and  antagonistic  to  the  action  of  the 
body  ferments.  Locally,  they  tend  to  depress  the  ends  of  the 
sensory  nerves. 

Poisoning. — Large  doses  so  affect  the  protoplasm  of  the  body 
that  it  is  unable  to  absorb  oxygen  from  the  blood.  As  a  conse- 
quence, the  venous  blood  is  like  the  arterial  blood,  i.  e.,  red  and 
oxygenated.  This  is,  so  far  as  we  know,  due  to  inhibition  of  the 
activity  of  the  oxidases  (oxidizing  ferments),  through  whose 
action  the  oxygen  of  the  blood  is  utilized  in  the  cells.  This 
property  of  cyanides  has  been  established  by  Richards  as  of 
value  in  the  study  of  the  action  of  certain  oxidizable  poisons. 

After  a  toxic  dose  of  cyanide  there  is  a  passing  stimulation 
of  the  vagus,  vasoconstrictor,  and  respiratory  centers,  followed  by 
marked  depression  of  these.  There  are  widely  dilated  pupils, 
and  vomiting  from  stimulation  of  the  pupil-dilating  and  vomiting 
centers,  then  convulsions,  probably  of  medullary  origin,  collapse, 
and  death  from  failure  of  the  respiraton.  Very  large  doses  taken 
when  the  stomach  is  empty  are  followed  almost  immediately  by 
a  few  convulsive  movements  and  death.  The  fatal  dose  is  vari- 


CONIUM  427 

able  because  of  differences  in  the  strength  of  preparations.  An 
amount  of  dilution  equivalent  to  about  i  minim  of  pure  hydro- 
cyanic acid,  or  2 1  grains  (0.16  gm.)  of  potassium  cyanide,  is 
reckoned  to  be  a  lethal  dose  (Taylor).  For  an  elephant  in  Cen- 
tral Park  it  required  9  ounces  (180  gm.)  of  potassium  cyanide  to 
produce  death.  The  poison  may  be  detected  by  the  characteris- 
tic odor,  which  is  perceptible  in  the  mouth  or  the  emptied  bottle, 
or  at  postmortem  on  opening  the  body. 

Treatment. — Prompt  emptying  of  the  stomach,  and  the  ad- 
ministration by  mouth  of  oxidizing  antidotes,  such  as  hydrogen 
peroxide,  potassium  permanganate,  or,  perhaps,  much  better, 
freshly  prepared  ferric  hydroxide  (the  arsenic  antidote).  Intra- 
venously i  per  cent,  sodium  hyposulphite,  and  0.5  per  cent,  co- 
baltous  nitrate  have  been  recommended.  In  addition,  are  indi- 
cated artificial  respiration  and  the  general  treatment  for  collapse. 

Therapeutics. — It  -has  been  employed  locally  to  allay  itching 
and  to  stop  nausea  and  vomiting.  It  is  also  used  to  check  cough. 
There  is  no  evidence  to  justify  its  employment  for  these  purposes, 
and  it  would  seem  that  the  medicinal  use  of  hydrocyanic  acid  or 
potassium  cyanide  might  with  advantage  be  abandoned. 

The  syrup  of  wild  cherry  is  much  used  as  a  flavor  in  cough 
mixtures.  Cherry-laurel  water  and  the  water  and  spirit  of  bitter 
almond  are  used  as  flavors. 

CURARE 

Curare,  containing  the  alkaloid  curarine,  is  a  South  American 
arrow-poison.  It  is  probably  obtained  from  a  species  of  Strych- 
nos,  the  genus  to  which  the  strychnine-yielding  plants  belong. 
Its  essential  action  is  to  paralyze  the  motor  end-plates  in  striped 
muscles,  and  for  this  purpose  it  is  largely  used  in  physiologic  and 
pharmacologic  laboratories.  It  has  been  used  in  certain  convul- 
sive or  spasmodic  conditions  of  striped  muscle,  but  its  dosage  is 
very  uncertain,  and  its  tendency  to  paralyze  the  respiratory 
muscles  is  marked,  hence  it  is  too  dangerous. 

CONIUM 

Conium,  or  "poison  hemlock"  (not  "hemlock"),  contains 
the  volatile  liquid  alkaloid,  coniine.  It  is  not  official,  but  the 
fluidextract  is  employed,  dose,  3  minims  (0.13  c.c.).  There  is 
some  medullary  depression  and  slight  sensory  depression,  but 
the  main  effect  is  a  curare-like  but  mild  depression  of  the  motor 
end-plates.  For  this  it  has  been  used  somewhat  in  certain 
spasmodic  nervous  affections,  such  as  chorea  and  whooping- 
cough,  but  has  been  found  of  little  value.  It  was  by  conium  that 


428  PHARMACOLOGY   AND   THERAPEUTICS 

Socrates,  the  philosopher,  was  put  to  death;  and  as  his  mind 
remained  clear  until  near  the  end,  he  wrote  a  description  of  his 
condition.  There  was  paralysis  with  slight  numbness,  beginning 
in  the  toes  and  gradually  ascending  until  it  involved  the  trunk. 
Death  from  conium  is  due  to  respiratory  paralysis,  either  of  the 
respiratory  center  or  of  the  terminals  in  the  respiratory  muscles. 

GELSEMIUM 

Gelsemium,  yellow  jasmine,  has  as  its  active  principle  the 
alkaloid,  gelseminine.  The  fluidextract,  dose,  i  minim  (0.06 
c.c.),  and  the  10  per  cent,  tincture,  dose,  10  minims  (0.6  c.c.),  are 
official. 

Peripherally  it  acts  like  conium,  but  centrally  is  more  de- 
pressing. It  is  somewhat  analgesic,  and  has  an  atropine  action 
on  the  pupil  and  accommodation.  Therapeutically,  it  has  been 
employed  with  reputed  good  effects  in  refractory  trifacial  neu- 
ralgia, but  just  how  it  checks  the  neuralgic  pain  has  not  been 
explained. 

SPARTEINE  SULPHATE 

Sparteine  sulphate,  dose,  i  grain  (0.06  gm.),  is  the  sulphate 
of  an  alkaloid  obtained  from  Scoparius,  or  broom.  It  slows  and 
weakens  the  heart  by  stimulating  the  ganglia  on  the  vagus  nerve 
and  by  directly  depressing  the  heart  muscle;  it  also  slightly  stim- 
ulates the  ganglia  of  the  vasoconstrictor  nerves.  Sparteine  was 
formerly  believed  to  have  a  digitalis  action,  but  laboratory 
experiments  prove  it  to  be  a  decided  cardiac  depressant. 

It  may  be  used  to  quiet  an  overacting  heart,  and  on  the  theory 
that  it  depresses  the  ganglia  of  bronchoconstrictor  nerves  may  be 
employed  in  spasmodic  asthma. 

LOBELIA 

Lobelia,  Indian  tobacco,  the  active  principle  of  which  is  the 
volatile  liquid  alkaloid  lobeline,  resembles  nicotine  or  real  to- 
bacco in  its  action.  Its  chief  use  is  in  spasmodic  asthma,  to 
depress  the  bronchomotor  nerve-endings  or  their  ganglia.  Small 
doses  taken  repeatedly  cause  an  unexplained  persistent  increase 
in  the  frequency  of  the  heart-beat.  The  fluidextract ,  dose,  2 
minims  (0.13  c.c.),  and  the  10  per  cent,  tincture,  dose,  20  minims 
(1.3  c.c.),  are  official.  The  leaves  are  a  constituent  of  some  of  the 
proprietary  asthma  powders,  which  are  used  for  burning,  the 
smoke  being  inhaled.  They  are  sometimes  made  into  cigars  or 
cigarettes  with  stramonium,  cubebs,  or  tobacco,  and  these  smoked 
during  an  asthmatic  attack.  Lobelia  has  also  been  employed  as  an 
emetic,  the  dose  required  being  four  times  that  mentioned  above. 


TOBACCO  (TABACUM)  429 

TOBACCO  (TABACUM) 

Tobacco  is  the  leaves  of  Nicotiana  tabacum  (Fam.  Solanacece), 
subjected  to  a  process  of  fermentation  to  remove  certain  proteins 
and  fats  that  would  make  the  smoke  disagreeable,  and  then  to 
another  process  of  fermentation  by  which  25  or  30  per  cent,  of  the 
nicotine  is  lost  and  the  aroma  developed.  The  chief  constituents 
of  the  cured  leaves  (not  the  smoke)  are  the  volatile  liquid  alkaloid, 
nicotine,  some  related  alkaloids,  and  a  volatile  oil  to  which  most 
of  the  aroma  is  due.  (For  the  constituents  of  the  smoke  see 
below.)  The  Havana  tobacco  is  noted  for  its  delicate  aroma,  and 
usually  contains  only  i  to  3  per  cent,  of  nicotine;  while  some  of 
the  Virginia  and  French  tobaccos  may  yield  as  much  as  6  or  7  per 
cent.  An  examination  of  Virginia  tobaccos  by  the  Virginia 
Agricultural  Experiment  Station  in  1898  showed  1.68  to  6.17  per 
cent,  of  nicotine.  Turkish  tobacco  comes  from  Nicotiana 
Rustica,  and  contains  about  2.5  per  cent,  of  nicotine  (Kew 
Bulletin). 

The  cured  tobacco  is  used  for  smoking;  or,  mixed  with  molas- 
ses, extract  of  licorice,  and  other  flavoring  materials,  is  used  for 
chewing  (chewing-tobacco).  When  powdered,  also  sometimes 
scented  and  flavored,  it  constitutes  snujj,  which  is  used  by  snuffing 
into  the  nose  or  rubbing  upon  the  gums. 

For  smoking,  tobacco  is  burned  in  a  pipe,  or  in  the  form  of 
cigarrete  or  cigar,  the  smoke  being  drawn  through  the  tobacco 
into  the  mouth,  or  sometimes  "inhaled,"  that  is,  drawn  into  the 
lungs.  A  method  of  drawing  the  smoke  through  water  or  rose- 
water,  as  in  the  "hookah,"  is  in  vogue  in  eastern  countries. 
It  is  said  that  this  takes  out  about  half  the  poison  and  cools  the 
smoke.  The  smoke  contains  nicotine,  pyridine,  quinoline,  hydro- 
cyanic acid,  irritant  aldehyds,  ammonia,  furfurol,  phenols, 
carbon  dioxide,  carbon  monoxide,  and  some  volatile  oil.  How 
much  of  the  nicotine  of  tobacco  is  destroyed  in  the  smoking  is  a 
question.  Allen  says  that  "the  greater  part  of  the  nicotine  is 
converted  into  pyridine  and  other  pyrogenous  compounds," 
and  Bush,  and  Vohl  and  Eulenberg  found  no  nicotine  at  all  in 
the  smoke.  As  pyridine  is  only  one-twentieth  as  poisonous  as 
nicotine  this  would  explain  the  absence  of  serious  acute  symptoms 
from  smoking.  Other  investigators,  however,  report  the  recovery 
from  the  smoke  of  one-  to  four-fifths  of  nicotine.  Lehmann  (1912) 
has  shown  that  the  hydrocyanic  acid  is  not  a  factor  in  the  tobacco 
effects;  but  the  investigations  of  the  London  Lancet  (1912)  point 
to  furfurol  aldehyd  and  other  aldehyds  as  harmful  constituents. 
Furfurol  is  a  constituent  of  the  fusel  oil  of  alcohol,  and  the  Lancet 
experiments  show  that  a  single  cigarette  may  contain  as  much  of 


430  PHARMACOLOGY  AND  THERAPEUTICS 

it  as  two  ounces  of  whisky.  Furfurol,  of  which  a  dose  of  ij 
grain  (o.i  gm.)  is  capable  of  producing  a  persistent  headache,  is 
practically  absent  from  the  smoke  of  Turkish  cigarettes. 

In  medicine,  tobacco  has  been  employed  externally  in  the  form 
of  a  poultice,  and  internally  as  an  emetic,  and  the  smoke  has  been 
inhaled  in  spasmodic  asthma;  but,  owing  to  its  great  toxicity  and 
to  the  great  difference  in  human  susceptibility  to  its  action,  it  is 
dangerous  as  a  remedy  and  has  been  omitted  from  the  Phar- 
macopoeia. Tobacco  is  still  used  more  or  less  in  asthma,  and  in 
addition  to  stramonium,  lobelia,  or  cubebs,  forms  a  constituent 
of  many  of  the  asthma  cigarettes  and  cigars.  As  its  value  is  so 
limited,  tobacco  is  to  be  considered  chiefly  because  of  the  effects 
of  the  tobacco  habit. 

The  world's  output  has  been  placed  at  2,000,000,000  pounds 
a  year.  In  the  United  States  alone  in  1913,  according  to  the 
internal  revenue  reports,  the  output  of  manufactured  tobacco 
was  410,976,513  pounds,  while  the  cigarettes  numbered  over 
15,000,000,000  and  the  cigars  over  8,500,000,000.  That  would 
be  over  4  pounds  of  tobacco  and  over  85  cigars  and  150  cigarettes 
for  each  inhabitant.  In  addition,  33,000,000  pounds  of  snuff 
were  manufactured. 

Pharmacologic  Action  of  Nicotine. — Nicotine  is  rapidly 
absorbed  from  skin  and  mucous  membranes.  Its  main  action 
is  a  brief  stimulation  of  the  cerebrum,  medulla,  and  cord,  of  the 
ganglia  on  the  vagus  and  sympathetic  nerves,  and  of  the  motor 
end-plates  in  voluntary  muscle,  the  stimulation  being  followed  by 
depression. 

Alimentary  Tract. — The  saliva  is  increased  and  there  may  be 
biting  of  the  tongue  from  the  irritant  nicotine.  Either  from  the 
local  effect  of  the  swallowed  saliva  or  from  its  systemic  effect 
after  absorption  there  may  be  nausea,  vomiting,  and  increased 
peristalsis  with  diarrhea. 

Circulation. — The  stimulation  of  the  vagus  center  and  ganglia 
results  in  a  slowing  of  the  heart,  and  that  of  the  vasoconstrictor 
centers  and  ganglia  in  a  great  rise  in  blood-pressure;  the  sub- 
sequent depression  shows  in  a  rapid  heart  and  lowered  blood- 
pressure.  From  smoking,  a  preliminary  rise  is  not  uncommon 
during  the  first  fifteen  or  twenty  minutes,  but  it  may  be  absent 
in  those  who  are  very  tolerant  of  the  drug.  To  one  who  is  not 
habituated  the  subsequent  fall  in  pressure  may  result  in  mild 
collapse.  A  fall  of  50  mm.  has  been  noted.  Cannon,  Aub,  and 
Binger  (1912)  have  shown  that  nicotine  can  cause  increased 
activity  of  the  adrenals. 

Respiratory. — This  center  is  also  stimulated,  then  depressed. 
The  bronchial  muscles,  from  stimulation  followed  by  depression 


TOBACCO  (TABACUM)  431 

of  the  ganglia  of  the  motor  nerves,  undergo  a  transient  contrac- 
tion, followed  by  persistent  relaxation;  hence  the  use  of  tobacco 
in  spasmodic  asthma. 

Smooth  muscle  of  all  kinds  is  affected  through  the  ganglia 
of  the  supplying  nerves. 

The  pupil  is  contracted  at  first  and  subsequently  dilated. 
This  is  from  an  effect  on  the  third-nerve  ganglia. 

The  cerebrum  is  only  slightly  stimulated,  and  this  effect  so 
quickly  passes  into  depression  that  the  drug  is  a  true  narcotic  or 
cerebral  sedative.  Tobacco  is  not  an  intellectual  stimulant,  but 
just  the  reverse. 

The  medullary  centers  and  the  reflexes  are  at  first  stimulated, 
then  depressed. 

Toxicology. — The  poisonous  effects  of  tobacco  (not  tobacco 
smoke)  are  due  chiefly  to  nicotine.  Two  drops  of  nicotine  placed 
on  the  tongue  or  rubbed  into  the  gums  of  a  small  dog  or  cat  will 
produce  death  in  one  or  two  minutes.  A  large  mastiff  died 
almost  instantly  when  ten  drops  were  placed  on  his  tongue,  and  a 
canary  when  one  drop  was  held  near  its  bill.  In  man  death  has 
followed  the  use  of  tobacco  as  a  poultice,  the  application  of  an 
infusion  in  skin  disease,  the  injection  of  an  infusion  into  the 
rectum  for  worms,  the  plugging  of  a  wound  with  a  quid  of  tobacco 
to  stop  the  bleeding,  etc.  In  fact,  a  cigar  may  contain  enough 
nicotine  to  kill  two  unhabituated  adults.  Fortunately  in  smoking 
the  nicotine  is  changed,  at  least  to  a  considerable  degree,  and 
much  of  that  present  is  exhaled  and  lost. 

Acute  nicotine  or  pyridine  poisoning  is  frequently  seen  after 
the  first  cigar,  or  when  an  unusually  large  quantity  of  tobacco  is 
consumed  in  a  short  time.  The  symptoms  are  those  of  mild 
collapse,  viz.,  pallor  of  the  skin,  sweating,  nausea,  and  perhaps 
vomiting,  diarrhea,  muscular  weakness,  faintness,  dizziness,  and 
lowered  arterial  pressure.  Tedeschi  reports  epileptic  seizures. 

Treatment. — Fresh  air  and  rest  lying  down,  with  reflex  stimu- 
lants, such  as  whisky,  brandy,  or  aromatic  spirits  of  ammonia. 
If  the  symptoms  are  severe,  the  treatment  is  that  for  severe 
collapse;  but  this  degree  of  poisoning  is  rare  from  smoking,  as  the 
stomach  symptoms  or  the  mild  collapse  come  on  early  and  check 
the  further  use  of  the  drug.  Were  the  drug  to  manifest  its 
symptoms  more  slowly,  so  that  a  larger  dose  might  be  consumed 
before  the  smoker  becomes  ill,  many  serious  poisonings  would 
result. 

Tolerance  is  readily  established  up  to  a  certain  limit,  which 
differs  widely  with  different  persons,  e.  g.,  the  limit  of  tolerance  for 
one  person  is  a  single  cigar  in  an  evening,  while  another  person 
may  smoke  ten  cigars  in  the  same  time  without  being  upset.  After 


432  PHARMACOLOGY   AND   THERAPEUTICS 

the  use  of  tobacco  has  been  abandoned  for  a  time  the  tolerance 
to  it  is  found  to  have  decreased. 

The  Tobacco  Habit. — As  a  habit  drug,  tobacco  is  peculiar  in 
that  the  effects  desired  are  not  to  be  attributed  in  any  great 
degree  to  its  most  active  constituent,  nicotine.  Indeed,  the  best 
tobaccos  are  not  by  any  means  those  with  the  highest  percentages 
of  the  alkaloid. 

To  the  beginner  in  smoking  the  pleasure  is  sadly  lacking;  and 
it  is  not  until  the  habit  is  established  that  smoking  becomes  a 
source  of  comfort  and  pleasure.  But  to  the  habitue  tobacco  is 
narcotic,  its  use  in  moderation  promoting  the  feelings  of  ease  and 
relaxation.  Strangely  enough,  its  pleasurable  effects  seem  quite 
unrelated  to  the  extent  of  the  physiologic  action,  for  to  most 
smokers  there  is  little  satisfaction  from  smoking  in  the  dark  or 
from  using  the  tobacco  in  some  unaccustomed  way,  as  in  a  pipe 
instead  of  cigarettes,  or  as  snuff;  and  a  weak  Havana  tobacco 
often  gives  more  pleasure  than  a  two  or  three  times  as  strong 
Virginia  or  Kentucky  variety.  It  is  a  fact,  also,  that  those  who 
have  the  habit  of  inhaling,  and  are,  therefore,  accustomed  to 
bringing  the  smoke  in  contact  with  a  large  surface  of  mucous 
membrane,  get  little  satisfaction,  no  matter  how  strong  the 
tobacco,  unless  they  inhale  to  bring  the  smoke  to  the  accustomed 
membranes.  The  same  may  be  said  of  the  use  of  tobacco  in 
the  form  of  snuff — smoking  will  not  satisfy  the  snuff  user. 

Another  noteworthy  fact  is  that  there  is  no  great  physiologic 
demand  for  the  usual  dose  of  tobacco,  so  that  the  habit  of  smok- 
ing can  be  stopped  suddenly  without  any  striking  physiologic 
reaction.  Also,  a  moderate  smoker — one  who  is  accustomed,  say, 
to  one  cigar  after  his  dinner — can  get  along  very  well  without  his 
smoke,  and  will  have  less  craving  for  it  two  or  three  hours  later 
than  he  had  at  the  usual  time  for  it.  This  is  not  true  of  morphine, 
cocaine,  or  the  other  habit  drugs,  for  which  the  craving  becomes 
worse  and  worse  as  the  deprivation  continues. 

It  is  evident,  then,  that  the  demand  for  tobacco  is  not  so 
much  the  physiologic  demand  of  the  body  for  its  dose,  as  it  is 
the  psychic  demand  for  the  satisfaction  of  a  habit.  The  smoker's 
pleasure  seems  to  be  derived  largely  from  the  presence  of  some- 
thing in  the  mouth,  from  the  studied  inhalation  and  exhalation, 
and  from  the  soft  circling  up  of  the  smoke.  The  fact  that 
the  presence  of  something  in  the  mouth  with  rhythmic  motion  of 
the  jaw,  as  in  gum-chewing,  gives  a  pleasure  that  is  similar, 
though  weaker,  places  the  use  of  tobacco  in  a  psychic  habit  class 
with  chewing  gum,  eating  chocolate,  or  perhaps  sucking  a  tooth- 
pick. In  attempting  to  break  the  tobacco  habit  we  take  advan- 
tage of  this  fact  and  advocate  the  chewing  of  gum,  or  of  some 


TOBACCO  (TABACUM)  433 

substance  of  strong  taste,  such  as  gentian  or  lovage,  or  the  eating 
of  candy  at  the  usual  smoking  time.  Many  an  old  smoker  speaks 
of  smoking  as  "a  fool  habit." 

That  the  effect  is  not  all  psychic,  however,  is  suggested  by  the 
failure  of  any  other  substance  to  give  the  satisfaction  that  tobacco 
does,  either  for  smoking  or  chewing.  Every  one  prefers  to  smoke 
tobacco,  for  example,  rather  than  cabbage  leaves,  though  the 
smoke  of  cured  cabbage  leaves  contains  pyridine  bases.  This 
preference  for  tobacco  may,  however,  be  merely  a  matter  of  the 
greater  delicacy  of  the  tobacco  taste  and  aroma. 

The  method  of  smoking  makes  some  difference.  The  Lancet 
has  shown  that  the  pipe  smoke  contains  the  most  alkaloid  and 
the  cigarette  smoke  the  least.  The  pipe  has  the  disadvantage 
that  owing  to  the  heat  of  the  tobacco  and  the  bowel  of  the  pipe, 
oily  nicotine  and  pyridine  substances  tend  to  distil  into  the  smoke 
without  combustion.  Some  of  these  are  inhaled  and  some 
accumulate  in  the  stem  of  the  pipe,  so  that  an  old  pipe  gets 
"strong."  The  pipe-smoker  tends  to  keep  more  or  less  under  the 
influence  of  tobacco  by  frequent,  short  smokes,  but  he  seldom 
inhales.  The  cigarette  smoker  is  prone  to  inhale,  i.  e.,  draw  the 
smoke  into  his  lungs. 

The  cigar  is  less  rapidly  consumed  than  the  cigarette,  and  its 
area  of  ignition  is  greater,  so  that  the  tobacco  just  in  advance  of 
the  area  of  combustion  gets  hot;  consequently  there  is  some  vol- 
atilization of  the  raw  nicotine,  and  this  is  drawn  in  with  the 
smoke.  This  is  not  so  much  as  in  the  pipe;  but  the  fatter  the 
cigar,  the  greater  will  be  the  volatilization,  and  therefore  the  less 
the  destruction,  of  the  nicotine.  Hence  the  smoke  of  a  thin  cigar, 
and  still  more  so  that  of  a  cigarette,  will  contain  less  of  the  raw, 
volatile  poisons  than  that  of  a  thick  cigar.  W.  E.  Lee  (1908) 
has  tested  the  relative  potencies  of  cigars  and  cigarettes  as  fol- 
lows: A  Manila  cigar  and  a  cigarette  of  Virginia  tobacco  of  nearly 
double  the  strength  of  the  Manila  tobacco  were  burned  so  that 
the  same  amount  of  tobacco  in  each  was  consumed  in  the  same 
time.  The  smoke  of  the  cigar  made  of  the  weaker  tobacco  was 
about  twice  as  toxic  as  that  from  the  cigarette. 

As  a  matter  of  fact,  the  cigarette  fiend  does  not  consume  any 
more  tobacco  than  the  cigar  or  pipe  fiend,  for  10  average  cigars 
represent  the  tobacco  of  50  or  60  cigarettes,  and,  as  we  have  seen, 
the  cigarette  is  the  least  harmful  form  of  tobacco.  Yet  there 
are  real  objections  to  the  cigarette,  viz.,  that  it  makes  smoking 
easy  for  the  young,  that  it  has  a  strong  tendency  to  induce  the 
habit  of  inhalation,  and  that,  being  small,  it  can  be  smoked  at 
odd  moments,  so  that  the  excessive  cigarette  smoker  tends  to 
keep  himself  under  some  influence  of  the  drug  all  day  long.  The 
28 


434  PHARMACOLOGY   AND   THERAPEUTICS 

charge  that  the  rice-paper  of  the  cigarette  produces  harmful 
fumes  has  been  repeatedly  shown  to  be  without  foundation. 
Indeed,  if  the  paper  is  impregnated  with  potassium  nitrate  to 
make  it  burn  evenly  and  without  bursting  into  a  flame,  as  is 
frequently  the  case,  it  has  a  tendency  to  overcome  the  primary 
rise  in  blood-pressure  which  is  brought  on  by  the  nicotine. 

Those  who  lead  an  open-air  life  can  smoke  much  more  than 
those  who  remain  indoors.  Especially  bad  is  constant  smoking  in 
an  ill- ventilated  room,  for  more  or  less  of  the  smoke  is  reinhaled. 

Moderate  smoking  is  a  psychic  depressant,  favoring  ease  and 
comfort  and  "laissez-faire,"  rather  than  effort  and  work  and 
energy.  It  is  truly  narcotic.  In  so  far  as  it  is  a  habit  the  smoker 
may  feel  ill  at  ease  if  he  fails  to  get  his  usual  smoke;  yet  excessive 
smoking  may  be  given  up  at  once  and  absolutely  without  any 
rebellion  on  the  part  of  the  body.  It  is  easier  for  the  patient  if  he 
keeps  away  from  smokers  and  has  cheerful  company,  and  if  he 
chews  something  bitter  or  strongly  flavored,  such  as  gentian-root, 
lovage,  chewing-gum,  or  chocolate. 

Blood- pressure. — Many  investigators  have  noted  a  decided 
rise  in  arterial  pressure  during  smoking,  even  in  persons  habitu- 
ated to  its  use.  But  this  is  not  a  constant  effect.  In  17  men 
from  sixteen  to  thirty-one  years  of  age,  Aikman  got  a  rise  in  5  and 
a  fall  in  12,  from  smoking  one  cigarette.  Thompson  and  Sheldon 
(1917),  experimenting  on  58  patients  in  middle  or  advanced  life 
with  high  arterial  pressure  and  arteriosclerosis,  found  that 
smoking  a  cigar  produced  a  rise  in  systolic  pressure  in  35  per 
cent.,  a  fall  in  45  per  cent.,  and  no  change  in  20  per  cent.,  the 
results  being  variable  in  the  same  patient. 

Efficiency. — Seaver  while  physical  director  at  Yale  estimated 
that  smoking  an  ordinary  cigar  resulted  in  one  hour  in  a  marked 
drop  in  muscular  po\ver.  Of  500  boys  at  school,  Taylor  found  the 
grades  of  the  smokers  invariably  lower  than  those  of  the  non- 
smokers.  Of  201  students  at  Clark  University,  of  whom  46.3  per 
cent,  were  smokers,  Clark  noted  that  68.5  per  cent  of  the  non- 
smokers  and  only  18.3  per  cent,  of  the  smokers  won  academic 
honors.  Meylan,  in  a  study  of  the  tobacco  habit  at  Columbia 
University,  concludes  that  "the  use  of  tobacco  by  college  stu- 
dents is  closely  associated  with  idleness,  lack  of  ambition,  lack  of 
application,  and  low  scholarship."  Of  course  one  must  concede 
that  the  men  of  poor  calibre  and  lack  of  application  are  more 
prone  than  ambitious  workers  to  carry  the  tobacco  habit  to  excess. 

Bush,  in  a  series  of  120  tests  in  each  of  fifteen  men  in  several 
different  psychic  fields,  shows  that  tobacco  smoking  was  followed 
by  a  10.5  per  cent,  decrease  in  mental  efficiency,  most  marked  in 
the  fields  of  imagery,  perception,  and  association.  Habituation 


TOBACCO  (TABACUM)  435 

lessened  the  degree  of  mental  inhibition  resulting  from  the  smok- 
ing, and  the  men  of  the  higher  intellectual  rank  seemed  to  have  the 
greater  susceptibility.  Fisher  and  Berry  found  that  even  a  single 
cigar  lessened  the  accuracy  of  baseball  players  in  throwing  a  base- 
ball at  a  target.  From  a  study  of  the  irritable  heart  of  soldiers, 
Parkinson  and  Koefod  (1917)  conclude  that  excessive  cigarette 
smoking  is  not  the  essential  cause  in  most  cases,  but  is  an  impor- 
tant contributory  factor  in  the  breathlessness  and  precordial  pain. 
Chronic  Tobacco  Poisoning. — Much  smoking  for  a  length  of 
time  may  cause  various  disturbances,  viz. : 

1.  Derangements  of  digestion,  as  lack  of  appetite,  nausea, 
heartburn,  constipation. 

2.  Headaches,  depressed  states  of  the  mind,  lack  of  energy, 
irritability  of  temper  (auto-intoxication),  restlessness,  nervous- 
ness, and  impaired  memory. 

3.  Tobacco  heart — rapid  or  slow,  irregular,  very  susceptible 
to   nervous   influence.     There   may   be   palpitation,   precordial 
distress,  and  dyspnea  on  exertion.    Syncope  may  cause  death  in 
high  altitudes,  and  a  number  of  persons  with  tobacco  heart  have 
died  in  the  train  while  crossing  mountains.     Tobacco-smoking 
has  been  the  cause  of  bradycardia,  tachycardia,  extrasystoles, 
auricular  fibrillation,  auricular  flutter,  sino-auricular  block,  and 
auriculoventricular  block. 

4.  Arteriosclerosis — atheroma  of  the  aorta  has  been  reported 
as  produced  in  rabbits  by  nicotine,  by  infusion  of  tobacco,  and 
by  inhalation  of  tobacco  smoke.     It  is  to  be  remembered  that 
atheroma  of  the  aorta  is  common  in  rabbits  without  tobacco. 

5.  Tobacco  amblyopia.     This  results  from  a  chronic  retrobul- 
bar  neuritis  in  which  it  may  not  be  possible  to  detect  anything 
wrong  with  the  optic  disc,  but  vision  is  dulled  and  is  not  im- 
proved by  glasses.     Vision  is  often  better  in  a  dull  light  than  in 
a  bright  one  (de  Schweinitz).     In  some  cases  the  optic  disc  may 
be  pale  and  somewhat  atrophied. 

6.  Deafness — either  from  the  production  of  catarrhal  con- 
ditions in  the  nasopharynx  and  Eustachian  tube,  or  from  an 
effect  on  the  nerve. 

Most  of  the  bad  effects  are  removed  by  the  stoppage  of  the 
drug  and  proper  hygiene,  i.  e.,  exercise,  fresh  air,  baths,  etc. 

The  local  irritation  of  the  smoke  upon  the  tongue  has  been 
charged  with  the  production  of  epithelioma;  that  on  the  throat 
with  the  production  of  catarrhal  conditions  or  hoarseness;  that 
of  the  swallowed  saliva  with  gastric  hyperesthesia  and  gastritis. 

Cigarmakers  show  a  high  proportion  of  cases  of  anemia, 
tuberculosis,  brachial  neuritis,  sciatica,  hysteria,  and  cardio- 
vascular affections. 


436  PHARMACOLOGY  AND  THERAPEUTICS 

THE  PERIPHERAL  NERVOUS  STIMULANTS 

We  have  already  spoken  of  the  peripheral  sympathetic  stimu- 
lation of  cocaine  and  epinephrine,  and  the  primary  stimulation 
from  nicotine. 

PHYSOSTIGMA  (CALABAR  BEAN) 

The  ripe  seed  of  Physostigma  venenosum  (Fam.  Leguminosce) , 
yielding,  when  assayed,  not  less  than  0.15  per  cent,  of  alkaloid 
soluble  in  ether.  The  plant  is  a  woody  twiner  of  western  Africa, 
and  the  calabar  beans  were  used  by  the  native  medicine  men  for 
"trial  by  ordeal."  The  person  accused  of  a  crime  was  given  a 
paste  made  of  the  seeds;  if  he  recovered,  he  was  declared  innocent; 
if  he  died,  he  was  guilty.  It  is  said  that  if  enough  cattle  were 
made  over  to  the  priests  they  were  prone  to  mistake  harmless 
seeds  for  the  calabar  in  making  the  paste. 

Constituents. — The  alkaloid  physostigmine  or  eserine  is  the 
essential  ingredient.  There  are  also  minute  quantities  of  two  or 
three  other  alkaloids,  of  which  eseridine  or  isophysostigmine  has 
the  action  of  physostigmine,  and  calabarine  that  of  strychnine. 
Physostigmine  in  solution  is  decomposed  by  light  or  heat,  and  a 
reddish  color  indicates  diminished  activity. 

Preparations  and  Doses. — 

Physostigma,  0.15  per  cent,  of  alkaloid;  dose,  i|  grains 

(o.i  gm.). 
Extract,  1.7  to  2.3  per  cent,  of  alkaloid;  dose,  f  grain 

(0.008  gm.). 
Tincture,  10  per  cent.,  15  minims  (i  c.c.). 

Physostigmine  salicylate,  soluble  in  75  parts  of  water  and  16 
of  alcohol,  is  given  in  dose  of  ^-^V  grain  (0.001-0.002  gm.). 

Pharmacologic  Action. — Physostigmine  stimulates  the  se- 
cretory nerve-endings  of  glands  and  the  nerve-endings  of  striated 
and  smooth  muscle.  It  therefore  antagonizes  the  effects  of  atro- 
pine  upon  secretion,  upon  the  action  of  smooth  muscle,  and  upon 
the  eye;  and  antagonizes  curare  in  its  effects  upon  striated  muscle. 
It  has  no  effect  on  sensory  nerve-endings. 

Secretion. — Physostigmine  is  not  employed  in  medicine  to 
increase  secretions,  for  by  arteriole  constriction  and  the  cutting 
off  of  the  blood-supply  of  the  glands  the  amount  of  the  secretion 
is  limited. 

Muscle. — Its  effect  upon  the  action  of  smooth  muscle  is 
strongest  in  the  alimentary  tract,  so  that  it  may  be  employed, 
either  by  mouth  or  hypodermatically,  as  a  cathartic.  It  also 
tends  to  cause  contraction  of  the  bladder,  ureters,  bronchi  and 
spleen,  and  perhaps  also  of  the  uterus. 


PHYSOSTIGMA    (CALABAR   BEAN)  437 

Its  effect  upon  the  action  of  striated  muscle  is  shown  in  the 
isolated  gastrocnemius  by  increased  irritability  and  increased 
power  to  lift  a  load.  Irregular  stimulation  in  man  is  also  indicated 
by  peculiar  fascicular  spasms  or  twitchings  of  the  muscle,  as  in 
the  temporal  or  orbital  muscles  when  the  drug  is  used  in  the 
eye,  or  in  the  muscles  of  the  limbs  in  poisoning.  It  is  directly 
antidotal  to  the  peripheral  action  of  curare,  and  presumably 
acts  upon  the  same  structures. 

The  Pupil. — If  a  drop  of  i  :  200  aqueous  solution  of  eserine  is 
placed  in  the  eye,  contraction  of  the  pupil  begins  in  one  or  two 
minutes  and  reaches  its  maximum  in  one-half  to  one  hour.  The 
marked  contraction  lasts  from  twelve  to  thirty-six  hours,  and  the 
normal  size  of  the  pupil  is  regained  in  from  two  to  four  days.  The 
contraction  is  due  to  stimulation  of  the  ends  of  the  third  nerves, 
physostigmine  not  contracting  the  pupil  after  degeneration  of  the 
nerve  (Anderson). 

Accommodation. — Through  similar  action  on  the  ends  of  the 
third  nerve,  the  ciliary  muscle  contracts  like  the  circular  muscle 
of  the  iris,  and  allows  the  lens  to  bulge  forward.  This  causes  the 
sight  to  be  fixed  in  accommodation  for  near  objects,  while  objects 
more  than  a  few  feet  away  are  out  of  focus.  There  is  sometimes 
supra-orbital  or  eyeball  pain  from  continued  overaction  of  this 
muscle.  The  accommodation  returns  to  normal  somewhat  more 
quickly  than  the  pupil. 

Intra-ocular  tension  is  much  lowered,  without  any  essential  pre- 
liminary rise  in  tension.  This  lowering  is  usually  considered  due 
to  the  increased  escape  of  fluid  through  the  spaces  of  Fontana, 
which  are  promptly  opened  up  by  the  contraction  of  the  pupil; 
but  Gronholm  attributes  much  of  the  fall  of  tension  to  contraction 
of  the  vessels  and  the  resulting  diminished  secretion. 

The  use  of  the  drug  in  the  eye  may  be  followed  by  disagree- 
able or  painful  twitchings  of  the  eyelid,  or  fascicular  spasms  of 
the  adjoining  face  or  temporal  muscles.  Physostigmine  is  much 
more  powerful  than  pilocarpine  as  an  antagonist  of  atropine. 

Circulation. — The  effect  upon  the  heart  and  arteries  is  but 
poorly  understood.  Small  doses  slow  the  heart,  and  as  this 
effect  follows  large  doses  of  atropine,  it  cannot  be  due  to  vagus 
center  stimulation.  Some  authors  believe  there  is  a  stimulation 
of  the  vagus  nerve-endings.  In  the  frog  there  are  direct  muscle 
stimulation  and  increased  irritability,  but  in  mammals  strengthen- 
ing is  not  usually  seen.  The  arterioles  are  contracted  from  per- 
ipheral stimulation,  probably  chiefly  of  the  ends  of  the  vaso- 
constrictor nerves,  for  Dixon  says  there  is  no  contraction  after 
apocodeine.  Arterial  pressure  is  raised.  There  is  apparently 
no  effect  upon  the  vasoconstrictor  center.  In  poisoning,  both 


438          PHARMACOLOGY  AND  THERAPEUTICS 

heart  muscle  and  vasoconstrictor  mechanism  are  depressed  so 
that  the  arterial  pressure  falls. 

Respiration  is  at  first  quickened  and  deepened,  from  stimula- 
tion of  the  center  and  probably  of  the  afferent  vagus  endings  in 
the  bronchi.  In  poisoning  there  is  depression  of  the  center,  and 
there  may  be  asthmatic  breathing  from  contraction  of  the  bron- 
chial muscles.  Death  is  due  to  failure  of  the  respiratory  center. 

Neroous  System. — The  cerebrum  is  little  affected,  conscious- 
ness in  fatal  poisoning  remaining  until  near  the  end.  The  vital 
medullary  centers  are  at  first  stimulated,  then  depressed.  The 
reflexes  are  depressed,  and  in  poisoning  there  may  be  an  ascend- 
ing paralysis,  beginning  in  the  legs.  The  effect  on  peripheral 
nerves  has  been  spoken  of;  there  is  no  effect  on  sensory  nerves. 

Excretion  is  rapid  by  the  urine.  A  slight  amount  appears  in 
the  saliva  and  bile. 

Toxicology. — Noteworthy  are  the  marked  muscular  weakness 
without  loss  of  consciousness.  The  pupils  are  markedly  con- 
tracted, the  skin  covered  with  sweat,  there  are  vomiting,  diarrhea, 
and  cramps  in  the  abdomen.  The  loss  of  muscular  power  begins  in 
the  legs  and  ascends,  and  is  accompanied  by  twitching  or  tremor. 
The  heart  is  at  first  slow  and  the  arterial  pressure  good ;  later  the 
heart  becomes  weak  and  slow,  and  the  blood-pressure  is  lowered. 
The  respiration  is  at  first  rapid  and  deep,  then  becomes  shallow 
and  labored  or  perhaps  asthmatic.  Death  occurs  from  paralysis 
of  respiration.  The  antidote  is  atropine  for  the  asthma,  the 
diarrhea,  and  the  intestinal  cramps;  if  necessary,  the  patiejit 
must  be  treated  for  collapse,  bearing  in  mind  that  the  heart  itself 
is  very  weak.  Joseph  and  Meltzer  recommend  magnesium  sul- 
phate as  partly  antidotal.  It  can  be  used  subcutaneously  or  in 
the  spinal  canal,  the  dose  being  i  dram  (4  c.c.)  of  a  25  per  cent, 
solution. 

Therapeutics. — The  extract  in  pills,  and  the  salts  of  physostig- 
mine  hypodermatically,  are  used  as  cathartics.  Since  not  many 
drugs  will  act  as  cathartics  when  administered  hypodermatically, 
a  knowledge  of  this  power  of  physostigmine  may  be  of  value  in 
some  severe  illnesses  or  postoperative  conditions. 

The  physostigmine  salts,  usually  in  a  solution  of  i  :  200, 
arc  much  employed  in  the  eye  to  lessen  the  high  intraocular 
tension  of  glaucoma,  and,  after  drugs  of  the  atropine  class, 
to  hasten  the  return  of  the  pupil,  accommodation  and  intraocular 
tension  to  normal.  They  are  preferred  to  pilocarpine  because 
their  action  lasts  longer  and  is  more  complete,  and  there  is  no 
noteworthy  preliminary  rise  of  intraocular  tension.  A  dis- 
advantage is  the  nervous  spasm  of  the  eyelid  and  temporal 
muscles,  which  may  occur  frequently  during  several  hours;  and 


PILOCARPUS    (jABORANDl)  439 

the  contraction  of  the  ciliary  muscles,  which  may  cause  a  blurring 
of  the  vision. 

Physostigmine  is  employed  as  an  antidote  in  magnesium 
sulphate  poisoning. 

PILOCARPUS  (JABORANDl) 

The  leaflets  of  Pilocarpus  jaborandi  or  of  Pilocarpus  micro- 
phyllus  (Fam.  Rutacece),  yielding,  when  assayed,  not  less  than- 
0.6  per  cent,  of  alkaloids.  It  is  a  Brazilian  shrub. 

Constituents. — The  alkaloid  pilocarpine,  also  isopilocarpine 
and  pilocarpidine,  with  similar  action,  and  jaborine,  which  acts 
like  atropine,  but  occurs  in  too  minute  quantity  to  have  any 
effect. 

Preparations  and  Doses. — 

Pilocarpus,  0.6  per  cent,  alkaloid;  dose,  30  grains  (2  gm). 
Fluidextract,  dose,  30  minims  (2  c.c.). 
Pilocarpine  hydrochloride  and  pilocarpine  nitrate;  dose,  \ 
grain  (o.oi  gm.),  the  former  being  readily  soluble  in 
alcohol  and  water,  the  latter  in  water  but  less  readily  in 
alcohol  (i  :  60). 

Pharmacologic  Action. — Pilocarpine  is  directly  antagonistic 
to  atropine  in  its  effects  upon  the  ends  of  the  secretory  nerves, 
the  ends  of  the  nerves  governing  smooth  muscle,  the  ends  of  the 
vagus  nerves,  and  the  ends  of  the  third  nerve  in  the  internal  eye. 
In  strong  solution  it  slightly  stimulates  the  gland  and  muscle 
cells.  It  does  not  affect  the  sensory  nerve-endings  or  the  striated 
muscle  or  their  motor  end-plates.  As  with  atropine,  pilocarpine 
acts  after  nerve  degeneration,  and  is  presumed  to  affect  a  material 
which  serves  as  receptor  of  nerve  impulses.  For  practical  pur- 
poses we  can  speak  of  its  acting  on  the  nerve-endings. 

Secretion. — The  secretion  chiefly  affected  is  that  of  the  sweat, 
pilocarpine  being  a  very  powerful  diaphoretic.  According  to 
Edmunds  and  Cushny,  a  man  may  lose  from  4  to  9  pounds  in 
weight  after  a  single  dose;  other  observers  also  have  estimated 
that  the  sweat  may  amount  to  a  gallon,  the  solid  as  well  as  the 
liquid  portion  being  increased  in  total  quantity.  The  sweating 
takes  place  after  the  nerves  to  the  glands  have  been  cut  peripheral 
to  the  ganglia,  so  the  drug  must  act  on  the  nerve-ending  or  the 
cell.  The  sweating  is  completely  checked  by  atropine.  As  it 
takes  much  more  atropine  than  normally,  it  is  believed  that  pilo- 
carpine stimulates  the  structures  that  atropine  depresses,  viz., 
the  receptor  substance  between  nerve-ending  and  muscle.  There 
is  some  evidence  that  pilocarpine  also  acts  slightly  on  the  ganglia. 
The  sweat  is  acid  or  neutral  from  the  fatty  acids  of  the  sebaceous 
secretion,  the  sebaceous  glands  sharing  in  the  stimulation. 


440  PHARMACOLOGY  AND  THERAPEUTICS 

The  saliva  and  bronchial  mucus  are  also  considerably  in- 
creased, and  to  some  extent  also  the  ear-wax  and  tears,  the  gastric, 
pancreatic,  and  intestinal  juices,  and  all  the  mucous  secretions. 
In  very  weak  conditions  the  bronchial  mucus  may  accumulate 
to  such  a  degree  as  to  interfere  with  the  breathing  and  favor  the 
development  of  edema  of  the  lungs.  All  these  secretory  effects 
are  prevented  by  atropine.  The  quantity  of  milk,  of  bile,  and  of 
urine  are  not  directly  affected.  It  is  stated  that  the  sugar  in  the 
blood  and  the  sugar  in  the  milk  are  increased  in  amount. 

It  is  an  interesting  fact  that,  both  from  the  local  application 
of  the  drug  to  the  scalp  and  its  internal  administration,  the  hair, 
in  some  cases,  increases  in  abundance.  This  result  is  due,  prob- 
ably, to  the  increase  of  the  scalp  secretions.  The  new  hair  may 
be  of  a  lighter  shade  and  give  a  patchy  appearance.  As  a 
test,  Pringle  (1908)  injected  \  grain  (0.03  gm.)  of  pilocarpine 
nitrate  into  the  scalp,  and  got  a  growth  of  hair  as  the  result. 

Smooth  muscle  shows  its  increased  activity  only  after  poisonous 
doses,  the  chief  manifestations  being  increased  peristalsis  in  the 
alimentary  tract  and  contraction  of  the  bronchi,  bladder,  and 
pupil.  The  effects  are  due  to  stimulation  of  the  nerve-endings, 
and  are  prevented  by  atropine.  The  arterial  muscles  are  not 
affected,  and  probably  not  the  uterus. 

The  Eye. — A  0.5  to  i  per  cent,  solution,  dropped  in  the  eye, 
has  the  following  effects: 

(a)  Pupil. — There  is  stimulation  of  the  third  nerve-endings, 
with  contraction  of  the  pupil,  the  maximum  contraction  being 
reached  in  one-half  to  one  hour,  and  lasting  only  three  or  four 
hours. 

(b)  Accommodation. — The  ends  of   the   third   nerve  in  the 
ciliary  muscle  are  stimulated;  hence  this  circular  muscle  con- 
tracts and  causes  bulging  of  the  lens  and  fixation  of  the  eye  in  ac- 
commodation for  short  distances.     There  may  be  a  dull  pain  from 
the  continued  muscular  contraction. 

(c)  Intraocular   Tension. — After  a  preliminary  rise,   lasting 
sometimes  as  much  as  half  an  hour,  and  probably  brought  on  by 
increased  secretion,  the  tension  falls.     The  fall  is  more  or  less 
coincident  with  the  pupil  contraction,  and  results  from  the  in- 
creased escape  of  fluid  which  follows  the  opening  of  the  lymphatic 
outlets  (spaces  of  Fontana)  when  the  pupil  contracts. 

Circulation. — From  large  closes  the  heart  is  usually  slowed 
and  slightly  weakened,  this  action  being  due  solely  to  stimulation 
of  the  vagus  endings,  and  being  preventable  by  atropine.  From 
very  poisonous  closes,  the  vagus  ends  may  become  paralyzed,  but 
the  heart  muscle  itself  is  directly  depressed,  so  that  the  beat 
continues  slow.  Sometimes  the  heart  beats  faster  at  first  from 


PILOCARPUS    (jABORANDl)  441 

vagus  center  depression.  After  toxic  doses  the  arterioles  are 
dilated  by  depression  of  the  vasoconstrictor  center,  and  blood- 
pressure  falls. 

Pilocarpine  is,  therefore,  a  cardiac  depressant,  both  vagus  and 
direct,  and  in  excessive  doses  an  arterial  dilator.  Its  margin  of 
safety  is  small,  and  its  administration  in  conditions  of  cardiac 
weakness  has  been  followed  in  some  cases  by  collapse  and 
death.  The  author  has  seen  two  cardionephritic  cases  die  from 
the  combined  effects  of  pilocarpine  hydrochloride,  T^  grain 
(0.006  gm.),  and  a  hot-pack. 

Respiratory  Tract. — Owing  to  the  increased  bronchial  secretion 
and  contraction  of  the  bronchial  muscles  from  stimulation  of  the 
ends  of  the  bronchomotor  nerves,  the  breathing  in  poisoning  may 
be  labored  or  asthmatic;  at  the  same  time  there  is  depression  of 
the  respiratory  center.  These  factors,  joined  to  weakness  of  the 
circulation,  tend  to  promote  edema  of  the  lungs,  asphyxia, 
collapse,  and  death. 

Nervous  System. — The  mind  remains  clear  in  pilocarpine 
poisoning,  but  there  is  depression  of  the  medullary  centers  and 
of  the  spinal  reflexes,  and  there  may  be  muscular  weakness  or 
paralysis. 

Elimination. — In  the  sweat,  urine,  and  saliva. 

Toxicology. — As  in  physostigmine  poisoning,  there  is  prostra- 
tion without  loss  of  consciousness.  There  is  at  first  excessive 
vagus  action  and  depression  of  the  vasoconstrictor  center,  with 
slowed  or  intermittent  heart-beat  (vagus  standstill  or  vagus 
heart-block)  and  low  blood-pressure.  Later  there  is  slow,  feeble 
heart-beat  and  collapse. 

The  pupil  is  strongly  contracted,  the  skin  flushed  and  pro- 
fusely sweating,  and  the  saliva  abundant.  There  may  be  nausea, 
vomiting,  diarrhea,  and  abdominal  cramps.  The  respiration  may 
be  labored,  asthmatic,  with  the  physical  signs  of  increased  bron- 
chial mucus  or  edema  over  both  lungs;  there  may  be  muscular 
relaxation,  beginning  in  the  lower  limbs  and  ascending.  Con- 
sciousness, though  dulled,  persists  until  near  the  end.  Death 
takes  place  in  collapse,  with  edema  of  the  lungs. 

The  treatment  is  atropine  hypodermatically,  and  the  general 
treatment  for  collapse,  especially  artificial  respiration.  The  atro- 
pine serves  to  overcome  the  asthmatic  breathing,  to  lessen  bron- 
chial secretion,  to  diminish  cramps  in  the  abdomen,  and  to  check 
excessive  vagus  action. 

Therapeutics. — The  fluidextract  is  added  to  hair-washes,  the 
pilocarpine  salts  being,  as  a  rule,  considered  too  expensive. 

In  the  eye,  a  i  :  200  solution  of  pilocarpine  hydrochloride  is 


442  PHARMACOLOGY   AND   THERAPEUTICS 

used  in  glaucoma,  and  to  hasten  contraction  of  the  pupil  after 
mydriatics. 

Internally,  it  has  been  employed  in  chronic  congestive  con- 
ditions of  the  middle  ear,  in  labyrinthine  affections,  and  in  con- 
gestive conditions  of  the  eye.  Its  good  effects  seem  to  depend 
largely  on  the  resulting  diaphoresis.  It  has  also  been  used  as  an 
expectorant  in  the  dry  stage  of  bronchitis,  but  it  makes  profuse 
sweating  and  salivation. 

Its  chief  use  is  as  a  diaphoretic  in  nephritis  with  uremia  and  in 
dropsy.  Tyson  recommends  10  minims  of  the  fluidextract  three 
times  a  day,  or  a  daily  dose  of  \  grain  of  pilocarpine  hydro- 
chloride.  Because  of  its  tendency  to  depress  the  heart  or  produce 
edema  of  the  lungs,  its  effects  must  be  watched;  and  it  should 
not  be  employed  if  the  heart  is  weak. 

MUSCARINE  AND  MUSHROOM  POISONING 

Muscarine  is  an  alkaloid  contained  in  the  mushroom  known 
as  the  fly  agaric,  Amanita  muscaria,  and  in  some  other  agarics. 
Its  actions  are  very  similar  to  those  of  pilocarpine,  but  stronger, 
hence  in  poisoning  by  the  fly  agaric  we  get  the  same  symptoms 
as  from  pilocarpine  poisoning.  The  symptoms  come  on  very 
quickly.  Muscarine  is  not  destroyed  by  cooking.  Atropine  is  the 
best  antidote,  and  the  stomach  should  be  washed  out  or  an  emetic 
given,  and  general  treatment  for  collapse  instituted.  Muscarine 
is  not  used  in  medicine,  as  it  is  more  dangerous  and  more  irri- 
tant to  the  stomach  than  pilocarpine. 

•  Most  of  the  cases  of  mushroom  poisoning,  however,  are  due  to 
the  death's-head  fungus,  Amanita  phalloides,  and  related  species, 
which  contain  little  if  any  muscarine,  but  depend  for  their  poison- 
ous action  upon  a  substance  which  has  the  nature  of  a  toxin.  It 
is  characteristic  of  a  toxin  that  the  symptoms  are  manifested  only 
after  a  latent  period,  and  that  immunity  may  be  established 
toward  it  in  susceptible  animals  by  the  repeated  administration 
of  non-lethal  doses.  This  toxin  is  destroyed  by  prolonged  cook- 
ing. Ford  has  prepared  a  serum  which  is  antitoxic  and  anti- 
hemolytic  to  the  amanita  toxin. 

The  symptoms  come  on  after  a  latent  period  of  ten  or  twelve 
hours.  They  are  great  thirst,  vomiting,  diarrhea,  cramps  in  the 
stomach  and  limbs,  headache,  cerebral  stimulation  up  to  a  state 
of  delirium,  and  sometimes  suppression  of  the  urine.  After 
twelve  to  twenty-four  hours  there  may  be  jaundice  from  extensive 
hemolysis,  or  collapse  from  a  toxic  action  upon  the  heart  muscle ; 
or  the  sickness  continues  for  several  days,  resembling  an  infectious 
disease.  Later  there  may  be  an  interstitial  nephritis  with  uremia. 


Fig.  54. — Amanita  phalloides,  white  form,  showing  cap,  stem,  ring,  and  cup.     (From 
Atkinson's  "Mushrooms,"  Henry  Holt  &  Co.,  Publishers.) 


'K-  55- — Agaricus  campestris.     View  of  under  side,  showing  stem,  ring,  gills,  and 
margin  of  rap.     (From  Atkinson's  "Mushrooms,"  Henry  Holt  &  Co.,  Publishers.) 


fj.  56. — Fly  amanita,  Amanita  muscaria.     Poisonous.     Nearly  one-half  natural 
size.     (From  Circular  139,  Third  Series,  U.  S.  Department  of  Agriculture.) 


DIAPHORETICS  443 

The  treatment  is  to  wash  out  the  stomach  and  the  colon,  apply 
an  ice-bag  to  the  head,  and  give  morphine  by  hypodermatic.  If 
collapse  ensues,  treat  for  collapse.  Atropine  is  of  no  value,  and 
Ford's  serum  would  hardly  be  obtainable  when  wanted. 

Ford  has  attempted  to  divide  the  poisonous  fungi  into  three 
groups,  viz. : 

1.  Those  containing  poisons  acting  on  the  nervous  system,  as 
Amanita  muscaria. 

2.  Those   producing  degenerative   changes   in   the   internal 
organs,  as  Amanita  phalloides,  Amanita  verna,  etc. 

3.  Those    causing   gastro-intestinal    irritation   with    violent 
manifestations,    as    Lactarius    torminosus,    Clitocybe    illudens, 
Entoloma  sinuatum,  etc. 

The  Amanita  muscaria,  or  fly  agaric,  is  highly  colored  with 
yellow  and  orange  and  reddish  tints.  Its  stem  is  longer  than  the 
diameter  of  the  cap,  bulges  at  the  base,  and  bears  a  collar  or  ring 
of  tissue.  The  cap  is  deep  yellow  or  orange  or  greenish  yellow, 
and  bears  numerous  scattered  white  or  yellow  scales.  The  gills 
on  the  under  surface  of  the  cap  are  white.  It  has  a  fungous  odor 
and  grows  in  open  woods  or  along  roadsides  near  trees. 

The  Amanita  phalloides  (death's-head  fungus,  deadly  agaric) 
is  white  throughout  or  slightly  brownish.  The  stem  often  arises 
from  a  cup — the  so-called  "death's-head"  or  "poison-cup"- 
bulges  at  the  base,  is  longer  than  the  diameter  of  the  cap,  and  near 
the  cap  is  surrounded  by  a  collar  of  tissue  (the  annulus  or  ring) ; 
it  tends  to  turn  dark  where  bruised.  The  cap  is  white,  or  slightly 
yellowish  or  greenish  white,  or  brownish,  and  its  under  surface 
bears  the  persistently  white  gills.  It  has  a  typical  fungous  odor, 
and  grows  in  open  woods  or  along  the  borders  of  woods. 

The  common  edible  mushroom  or  field  mushroom  is  Agaricus 
campestris.  It  is  stubby  in  growth.  Its  stem  is  shorter  than  the 
diameter  of  the  cap,  is  cylindric,  and  instead  of  being  bulbous  is 
narrowed  at  the  base;  it  does  not  emerge  from  a  cup,  and,  except 
for  the  first  hour  or  two  after  maturity,  is  usually  without  an 
annulus  or  ring.  Its  cap  is  white  to  brownish,  and  bears  on  its 
under  surface  the  notably  pink  gills,  which  become  purplish 
brown  when  a  few  hours  old,  and  turn  blackish  brown  on  keeping. 
It  has  an  earthy  smell,  like  potatoes,  rather  than  a  fungous  smell, 
and  grows  in  fields,  lawns,  or  by  roadsides. 

DIAPHORETICS 

A  diaphoretic  is  a  remedy  which  tends  to  induce  profuse 
sweating.  Profuse  sweating  is  diaphoresis. 

The  measures  employed  to  produce  diaphoresis  are  either  drugs 


444  PHARMACOLOGY   AND   THERAPEUTICS 

or  methods  of  raising  and  keeping  raised  the  body  heat.  We  do 
not  here  consider  terror,  nausea,  great  weakness,  and  other  causes 
of  profuse  sweating,  as  these  are  not  therapeutic  agents. 

1.  The  drugs  in  common  use  are:  pilocarpine,  whisky,  Dover's 
powder  (pulvis  ipecacuanhas  et  opii),  the  spirit  of  Mindererus 
(liquor  ammonii  acetatis),  and  the  sweet  spirit  of  niter  (spiritus 
aetheris  nitrosi),  all  of  which  we  have  already  studied.     Many 
other  drugs  tend  to  increase  the  sweat,  but  are  not  employed  for 
that  express  purpose  in  therapeutics. 

2.  Methods  of  raising  body  heat  and  keeping  it  raised  for 
diaphoretic  purposes: 

(a)  Increasing  the  production  of  heat,  as  by  exercise. 

(6)  Prevention  of  heat  loss,  as  with  blankets  or  extra  bed- 
clothes, or  heavy  woolen  sweaters,  as  during  exercise. 

(c)  The  use  of  artificial  heat,  either  internally  or  externally — 
internally,  by  hot  drinks,  and  externally,  by  hot  air,  hot  baths, 
vapor  baths,  electric  baths,  etc.  A  full  Turkish  bath  involves 
remaining  about  five  minutes  in  a  room  at  230°  F.  (110°  C.), 
five  minutes  at  i9O°F.  (8y.80C.),  and  fifteen  or  twenty  minutes  at 
about  140°  F.  (60°  C.),  the  air  being  kept  as  dry  as  possible  by 
good  ventilation.  A  Russian  bath  is  similar,  but  the  air  is  sur- 
charged with  aqueous  vapor  by  steam. 

Water  taken  internally  is  both  diaphoretic  and  diuretic.  It 
is  not  cathartic  (except  perhaps  in  those  who  habitually  under- 
drink),  for  the  intestines  can  absorb  such  enormous  quantities 
that,  in  normal  conditions  at  least,  the  excess  does  not  pass  out 
by  the  rectum,  but  is  excreted  by  the  kidneys  and  skin  (Starling). 
Cold  water  alone  is  essentially  diuretic  rather  than  diaphoretic, 
the  sweat  being  increased  to  only  a  slight  degree.  But  large 
drinks  of  hot  water,  as  in  the  form  of  hot  lemonade  or  chamomile 
tea,  or  large  drinks  of  cold  water  plus  measures  which  increase 
body  heat  and  set  in  action  the  heat-regulating  mechanism 
(as  hot  air,  hot  baths,  exercise,  etc.),  result  in  a  copious  out- 
pouring of  sweat. 

It  is  our  custom  in  therapeutics  to  combine  the  measures. 
For  example : 

1.  In  exercising  to  remove  fat  a  sweater  or  two  is  worn  to 
prevent  heat  loss  by  evaporation  of  the  sweat. 

2.  To  check  a  cold,  a  liberal  draft  of  hot  lemonade  or  water  at 
bed-time,  with  or  without  whisky,  is  assisted  by  extra  bed-cloth- 
ing, and  sometimes  a  preliminary  hot  bath. 

3.  In  nephritis  and  dropsical  conditions  the  hot-pack  or  hot- 
air  bath  is  employed,  with  sometimes,  in  addition,  a  hypoder- 
matic of  pilocarpine  hydrochloride,  y1^  grain  (0.006  gm.). 

The  hot-pack  gives  a  combination  of  increased  external  heat 


DIAPHORETICS  445 

with  prevention  of  heat  loss.  In  giving  a  hot-pack  the  patient, 
all  except  the  head,  is  wrapped  in  a  blanket  or  sheet  (the  arms 
being  separated  from  the  body  by  a  layer  of  material) ,  then  suc- 
cessively in  two  blankets  which  have  been  wrung  out  of  very  hot 
water,  then  perhaps  in  a  rubber  sheet,  with  the  bed-clothes  over 
all.  He  is  kept  thus  for  from  fifteen  to  thirty  minutes.  If  the 
hot-pack  is  not  for  dropsy,  a  copious  drink  of  water  or  lemonade 
may  be  administered;  if  it  is  for  dropsy,  liquid  must  not  be  given. 
To  prevent  headache,  an  ice-bag  or  wet  cold  cloth  should  be 
applied  to  the  head.  In  dyspneic  conditions  the  pack  should  not 
be  extended  high  on  the  chest. 

The  electric  bath,  the  hot-air  bath,  and  the  vapor  bath  are 
sometimes  used  for  the  same  purposes.  The  electric  bath  is  given 
in  a  cabinet  in  which  the  patient  sits  (head  out),  surrounded  by 
electric  lights.  In  the  hot-air  and  vapor  baths  the  patient, 
wrapped  in  a  sheet,  sits  in  a  cabinet  or  tent  with  the  head  out;  or 
if  in  bed,  may  have  a  sheet  hung  over  him  in  the  form  of  a  tent. 
A  heater  in  the  tent  or  cabinet,  or  hot  air  conducted  into  the  tent 
by  a  pipe,  makes  a  hot-air  bath;  the  steam  from  a  kettle  makes  a 
vapor  bath.  Cold  applications  to  the  head  during  these  baths 
tend  to  prevent  headache. 

By  any  of  these  methods  copious  sweating  is  produced,  even 
to  the  amount  of  several  quarts ;  and  if  the  skin  is  not  exposed  to 
cold,  the  production  of  sweat  may  continue  above  normal  for  as 
much  as  twenty-four  hours.  If,  however,  sweating  does  not 
result,  there  may  be  headache  and  feelings  of  faintness,  and  even 
collapse,  as  sometimes  occurs  in  the  Turkish  bath.  Even  when 
there  is  profuse  sweating,  collapse  sometimes  takes  place  in  a  hot- 
pack,  and  especially  is  this  likely  after  pilocarpine;  so  in  serious 
heart  conditions,  or  if  there  is  a  tendency  to  edema  of  the  lungs, 
diaphoretic  measures  must  be  used  with  caution.  Nevertheless, 
as  a  rule,  profuse  sweating  is  not  so  exhausting  as  repeated  ca- 
tharsis. 

During  or  immediately  following  a  copious  sweat,  exposure  to 
cold  may  result  in  chilling  of  the  surface,  with  contraction  of  the 
skin  vessels  and  internal  congestion,  i.  e.,  a  cold.  Therefore,  be- 
fore going  out  after  a  heavy  sweat  one  should  have  a  cold  sponge 
or  shower  with  a  good  rubbing  down  of  the  skin  and  a  short 
period  of  rest. 

The  Rationale  of  Sweating. — Normally,  the  loss  of  heat 
through  the  skin  is  due  to  radiation  and  convection  from  the  sur- 
face of  the  body,  and  to  the  cooling  effect  of  the  evaporation  of 
sweat.  Radiation  and  convection  are  promoted  by  cold,  and  by 
dilatation  of  the  skin  vessels,  as  in  exercise;  but  it  is  largely  by 
sweating  that  the  heat  loss  of  the  body  is  normally  increased. 


446  PHARMACOLOGY  AND  THERAPEUTICS 

Ordinarily  the  evaporation  of  the  sweat  keeps  pace  with  its 
production,  so  that  the  sweat  does  not  gather  into  perceptible 
moisture.  But  when  the  sweat  cannot  evaporate  as  rapidly  as 
it  is  produced,  as  during  exercise,  or  in  a  humid  atmosphere,  or 
for  other  reasons,  the  perspiration  collects  and  becomes  visible. 
Perspiration  that  is  visible  indicates  that  the  heat-regulating 
mechanism  has  overdone  the  production  of  sweat,  and  that  more 
is  produced  than  under  the  existing  circumstances  can  be  utilized 
for  cooling  purposes. 

When  the  surrounding  medium  is  hotter  than  the  body,  as  in 
these  hot-bath  methods,  radiation  and  convection  are  abolished, 
and  consequently  the  only  cooling  mechanism  left  is  sweating. 
But  as  the  heat-regulating  centers  do  not  discriminate,  the  sweat 
continues  to  form  so  long  as  the  body  is  hotter  than  normal,  even 
though  the  conditions  are  such  that  the  sweating  cannot  serve 
its  usual  purpose  in  cooling  the  body.  Just  so  long,  therefore,  as 
there  is  a  heightened  body  temperature  the  sweating  continues, 
in  a  futile  attempt  of  the  heat-regulating  mechanism  to  bring 
the  body  temperature  to  normal  in  the  usual  way. 

In  the  methods  for  inducing  diaphoresis  it  is  this  tendency  of 
the  sweating  mechanism  to  respond  to  raised  body  heat  of  which 
advantage  is  taken.  For  so  long  as  the  sweat  is  prevented  from 
accomplishing  its  object  of  cooling  the  body,  the  sweating  will 
continue  indefinitely.  Hence  the  use  of  exercise,  hot  drinks,  and 
hot-air  and  hot-water  baths  to  increase  the  body  heat;  and  of 
blankets,  sweaters,  etc.,  to  lessen  the  heat  radiation  and  to 
absorb  the  sweat  and  prevent  its  evaporation  at  the  surface  of 
the  body. 

Fat. — In  a  sense  there  is  a  protective  garment  about  a  fat  per- 
son, the  thick,  poorly  conducting  layer  of  fat  interfering  with  heat 
loss;  so  that  if  the  internal  temperature  is  raised,  an  excessive 
amount  of  sweat  is  poured  out  in  the  effort  of  the  body  to  cool 
itself.  On  a  hot,  dry  day  a  fat  man  may  lose  by  evaporation 
as  much  as  3200  calories;  on  a  hot,  humid  day  a  fat  man  sweats 
more  profusely,  yet  suffers  more  from  the  heat  than  the  thin  man. 
If  a  fat  person  ingests  no  water  while  carrying  out  diaphoretic 
measures,  the  body  tends  to  form  water  from  the  fat,  and  so  lessen 
its  adipose  deposit.  Von  Noorden  says  that  100  grams  of  fat 
yield  107  grams  of  water,  and  he  states  that  restriction  of  the 
water  intake  produces  a  loss  of  fat.  But  he  quotes  Heilner  and 
also  Henneberg  as  authorities  for  the  statements  that  in  experi- 
mental animals  abundant  water-drinking  increases  fat  catabolism, 
and  in  stock-raising  renders  it  very  difficult  to  fatten  animals. 
Hawk  says  that  water  increases  protein  metabolism.  Yet  by 
vigorous  daily  exercise,  wearing  heavy  sweaters,  limitation- 


DIAPHORETICS  447 

of  the  fluids,  and  regulation  of  the  food  ingested  a  fat  man  may 
lose  40  or  50  pounds  of  his  weight  in  a  few  months  and  yet  feel  in 
splendid  condition. 

The  Character  of  the  Sweat  in  Diaphoresis. — The  normal  se- 
cretion of  the  sweat-glands  is  of  low  specific  gravity  and  of  faintly 
alkaline  reaction,  and  there  are  various  salts  present.  The  slight 
acidity  sometimes  noted  is  due  to  admixture  with  the  fatty  acids 
of  the  sebaceous  secretion.  It  is  frequently  stated  that  the 
copious  sweat  produced  by  methods  to  raise  body  heat  is  slightly 
alkaline,  but  in  many  tests  by  the  author  of  the  sweat  of  nephritics 
in  the  hot-pack  it  has  been,  without  exception,  acid. 

The  Relation  of  Diaphoresis  to  Nitrogenous  Excretion. — The 
ordinary  insensible  perspiration  does  not  contain  any  appreciable 
nitrogenous  matter  (Lusk).  The  average  of  many  tests  by  dif- 
ferent experimenters  gives  0.068  gm.  nitrogen  per  day  in  skin 
elimination. 

Benedict  (1906)  got  0.071  gm.  nitrogen  per  day  in  the  whole 
cutaneous  secretions,  both  sebaceous  and  sweat,  of  a  resting  man. 
"But  when  the  sweat  was  increased,  as  in  a  man  at  moderate 
work,  the  nitrogen  from  the  skin  rose  to  0.13  gm.  per  hour,  and  in 
a  man  at  hard  work  to  0.22  gm.  per  hour.  The  nitrogen  of  these 
larger  quantities  represented  urea,  uric  acid,  creatinin,  and  other 
constituents  of  urine."  Therefore,  copious  sweating  from  hard 
work,  which  Atwater  and  Benedict  found  might  be  eight  times  the 
normal  sweating,  represented  the  loss  of  i  gm.  of  nitrogenous 
excreta  in  five  hours.  This  shows  that  the  sweat-glands  of 
normal  persons  can,  to  some  degree,  be  made  to  take  on  a  func- 
tion of  the  kidneys.  But  in  this  work  there  was  greatly  increased 
muscular  activity,  i.  e.,  increased  metabolism,  and  consequently 
the  results  are  not  indicative  of  the  real  excretory  value  of  diapho- 
resis in  sick  people. 

Some  of  the  striking  experiments  on  diaphoresis  are  worth 
noting: 

Hoelscher,  in  22  experiments  with  hot-air  baths,  obtained 
6719  c.c.  of  sweat,  containing  a  total  nitrogen  of  0.48  gm.  per 
looo  c.c.  Eijkmann  studied  three  medical  students  at  light  occu- 
pation in  the  climate  of  Java.  In  three  hours  he  obtained  0.222 
gm.  nitrogen;  in  twenty-four  hours,  0.761  and  1.362  gm.  nitrogen. 

Benedict  experimented  with  a  man  twenty-four  years  old,  75 
kilos  in  weight,  at  rest  in  the  respiration  chamber  during  four  days 
of  fasting  and  then  three  days  with  food.  The  average  daily 
nitrogen  excreted  by  the  skin  was  0.103  Sm-  When  such  a  man 
did  eight  hours'  work  on  a  stationary  bicycle  in  the  respiratory 
calorimeter,  his  clothes  extracted  with  distilled  water  gave  an 
average  of  0.29  gm.  nitrogen  per  day  for  eighty-eight  days'  work. 


448  PHARMACOLOGY   AND   THERAPEUTICS 

Lawnius  estimated  that  in  a  circus  athlete  the  loss  in  the 
sweat  was  1.8  gm.  nitrogen  per  day.  Zuntz  calculated  that  the 
loss  of  nitrogen  to  the  perspiration,  including  shed  epithelium,  is 
0.46  gm.  per  day. 

Atwater  and  Benedict  with  a  professional  bicyclist  twenty- 
eight  years  of  age  and  62  kilos  in  weight,  placed  in  the  bicycle 
ergometer  for  four  hours,  found  that  the  heat  output  was  about 
600  calories  per  hour,  and  that  the  total  nitrogen  increase  in  the 
sweat  was  roughly  proportional  to  the  work  done. 

In  the  sweat  of  6  normal  humans  and  3  nephritics  Riggs 
(1911)  failed  to  find  uric  acid.  But  Plaggemeyer  and  Marshall 
(1914)  tested  normal  passive  sweat,  obtained  during  25  min- 
utes of  hot-air  sweating,  and  filtered  to  eliminate  shed  epithe- 
lium, and  found  urea,  uric  acid,  ammonia,  and  diastase  as  con- 
stant constituents,  the  urea  being  0.05-0.3  per  cent,  and  the  uric 
acid  0.00005-0.00018  per  cent.  The  total  output  of  nitrogen 
ranged  from  34  to  640  mg.,  the  ratio  of  ammonia  nitrogen  to  the 
total  nitrogen  being  considerably  higher  than  that  in  the  urine. 

In  Sickness. — In  uremia,  a  condition  of  poisoning  in  which 
the  molecular  concentration  of  the  blood  is  increased  as  a  result 
of  impaired  kidneys,  the  sweat  poured  out  may  contain  a  much 
greater  proportion  of  nitrogenous  material  than  that  from  hard 
work.  In  fact,  in  nephritis  crystals  of  urea  have  actually  been 
found  deposited  upon  the  skin ;  though  this  was  only  in  terminal 
conditions  of  collapse  with  abnormal  capillary  permeability. 
That  in  uremia  profuse  sweating  is  of  great  value  in  carrying 
off  nitrogenous  material  was  the  contention  of  Bendix  (1904), 
who  claimed  to  be  able,  by  profuse  sweating  alone,  to  bring  to 
normal  the  greatly  depressed  freezing-point  of  the  blood  of 
uremic  patients,  i.  e.,  to  reduce  its  molecular  concentration  to 
normal.  But  Austin  and  Miller  (1914)  observed  no  effect  from 
sweat-baths  on  the  non-protein  nitrogen  of  the  blood  in  nephritics 
with  hypertension. 

Tachau  (1912)  gave  one-hour  sweat-baths  to  nephritics  and 
determined  that  the  nitrogen  excreted  amounted  to  0.2  to  0.49 
gm.,  while  the  chlorides  were  1.31  to  2.05  gm.  Von  Noorden 
says  that  the  perspiration  of  nephritics  contains  a  maximum  of  i 
to  1.3  gm.  of  urea  from  profuse  sweating,  and  this  is  too  little  to 
be  of  moment  to  the  kidneys.  Thus  from  an  excretion  point  of 
view  sweating  in  nephritis  must  be  considered  chiefly  of  use  in  re- 
moving water  and  perhaps  chlorides  rather  than  urea  or  other 
nitrogenous  waste.  But  by  draining  the  blood  of  water  it  has  the 
additional  effect  of  mobilizing  the  tissue  fluids,  of  promoting  the 
visceral  circulation,  and  perhaps  also  of  bringing  into  the  blood 
antibodies  to  be  utilized  or  toxins  to  be  excreted.  Hunt  has 


DIAPHORETICS  449 

demonstrated  that  normally  the  reserve  of  water  in  the  body  is 
so  great  that  even  when  several  liters  of  water  have  been  lost 
by  sweating,  the  percentage  of  water  in  the  blood  is  not  appreci- 
ably diminished  because  of  supply  from  the  tissue  fluids.  More- 
over, the  dilatation  of  the  skin  vessels  results  in  a  diversion  of 
the  blood  from  the  congested  internal  organs. 

In  intestinal  putrefactive  toxemia  with  indicanuria,  indol  has 
been  detected  in  the  perspiration. 

By  the  chlorides  excreted  Spitta  has  determined  that  sweat- 
ing is  as  great  in  a  hot  bath  as  in  hot  air  of  the  same  temperature; 
therefore  by  a  simple  hot  bath,  as  by  the  more  elaborate  baths, 
profuse  sweating  may  be  produced,  and  afterward  may  continue 
for  many  hours  in  excess  of  normal  if  the  person  remains  in  a 
warm  room  or  in  bed. 

Therapeutics  and  Administration. — i.  To  lower  temperature, 
in  mild  fevers — the  liquor  ammonii  acetatis,  2  drams  (8  c.c.), 
or  spiritus  setheris  nitrosi,  i  dram  (4  c.c.).  The  effect  of  these 
is  probably  almost  nothing. 

2.  To  overcome  chill  or  cold — by  relieving  internal  congestion 
and  reestablishing  proper  cutaneous  circulation.     Hot  lemonade 
at  bedtime,  whisky  and  hot  water,  Dover's  powder,  and  a  hot 
bath  are  the  favorites,  with  extra  bed-clothes.     Dover's  powder 
is  in  extensive  use  by  both  physicians  and  the  laity  to  produce 
sweating,  especially  if  there  is  pain  or  restlessness.     But  unless  it 
is  given  with  a  copious  hot  drink  and  the  patient  uses  extra  bed- 
clothing,  the  chances  of  its  producing  profuse  sweating  are  very 
small.     It  is  given  in  5  or  lo-grain  doses,  and  is  often  followed 
the  next  morning  by  nausea,  headache,  and  a  feeling  of  lassitude. 

3.  To  lessen  obesity — exercise  with  heavy  woolen   clothing, 
Turkish  baths,  hot  baths,  restriction  of  liquids  ingested. 

4.  To  assist  the  kidneys  in  the  removal  of  accumulated  poisons, 
as  in  uremia,  and  possibly  in  gout,  rheumatoid  conditions,  eclamp- 
sia, and  other  toxemias.     Hot-pack,  vapor  baths,  etc.,  with  or 
without  pilocarpine,  and,  if  there  is  no  edema,  with  copious 
drafts  of  water.     A  hot-pack  is  often  followed  by  a  decided  in- 
crease in  kidney  activity. 

5.  To  lessen  edema  and  promote  the  absorption  of  dropsical 
effusions — hot-pack,  vapor  baths,  etc.,  with  dry  diet,  very  little 
water  being  ingested;  sometimes  with  pilocarpine.     It  must  be 
understood,  of  course,  that  dropsical  fluid  is  reabsorbed  from  the 
tissue  spaces  when  by  sweating  the  blood  loses  water.     An  added 
factor  in  lessening  edema  may  be  the  excretion  of  sodium  chloride 
in  the  sweat. 

6.  To  lessen  congestion  of  the  internal  eye  and  of  the  middle 
and  internal  ear — especially  by  pilocarpine. 

29 

\ 


450  PHARMACOLOGY  AND  THERAPEUTICS 

7.  To  hasten  the  outbreak  of  the  rash  in  measles  and  other  exan- 
themata. Hot  baths  for  this  purpose  are  in  common  employ- 
ment. 

Local  sweating  with  high  temperature  is  used  in  chronic 
rheumatism,  rheumatoid  and  gonorrheal  arthritis,  and  other  joint 
affections.  In  the  ordinary  baking-box  for  an  arm  or  a  leg,  such 
as  Bier's,  the  temperature  can  be  borne  for  half  an  hour  up  to 
about  1 80°  F.,  the  heat  of  a  baking  oven,  and  this  induces  a 
marked  hyperemia  of  the  limb,  with  profuse  perspiration.  With 
the  Sprague  apparatus,  in  which,  by  a  special  arrangement,  the 
evaporation  of  the  perspiration  keeps  pace  with  its  production  so 
that  there  is  never  any  visible  perspiration,  a  temperature  of 
300°  to  350°  F.,  the  so-called  "superheated  air,"  can  be  borne 
without  discomfort  or  burning.  At  this  temperature,  if  a  drop 
of  water  should  collect  on  the  skin,  it  would  instantly  form  steam 
and  scald  the  skin.  A  limb,  or  even  the  whole  body  except  the 
head,  can  be  kept  at  this  temperature  for  fifteen  or  twenty 
minutes,  the  body  temperature  rising  from  i  to  4  degrees.  Cold 
applications  should  be  kept  upon  the  head. 

DIURETICS 

A  diuretic  is  a  remedy  which  tends  to  promote  the  flow  of 
urine.  Diuresis  is  copious  flow  of  urine. 

The  kidney  is  a  highly  vascular  organ,  with  numerous  vaso- 
motor  nerves  and  readily  influenced  arterioles.  Its  function  is 
to  preserve  the  normal  composition  of  the  body  fluids  by  ridding 
the  blood  of  certain  substances  which  are  present  in  excess  or  are 
not  normal  constituents,  hence  it  reacts  readily  to  changes  in  the 
blood  composition. 

The  blood  from  the  renal  artery  passes  along  the  afferent 
arterioles  into  the  capillaries  of  the  glomeruli,  and  there  loses  a 
certain  amount  of  water,  containing  substances  in  solution.  This 
escapes  through  the  endothelium  of  the  capillaries  and  their 
covering  membrane  of  Bowman's  capsule  into  the  uriniferous 
tubule;  while  the  blood,  thus  concentrated,  leaves  the  glomerulus 
by  an  afferent  vein,  which  is  smaller  than  the  afferent  arteriole 
(perhaps  only  two-thirds  the  size).  "This  vein  divides  into 
branches  after  the  manner  of  an  artery,  and  from  these  arises  a 
dense  network  of  capillaries  which  everywhere  ramify  over  the 
wall  of  the  uriniferous  tubule"  (Quain).  The  blood  in  the  capil- 
laries surrounding  the  tubule  is,  therefore,  blood  with  a  diminished 
total  of  dialyzable  substances  and  concentrated  by  the  loss  of 
water;  and  it  differs  by  so  much  from  the  blood  in  the  capillaries 
of  the  glomeruli. 


DIURETICS  451 

The  average  daily  urine  amounts  to  about  1500  c.c.,  is  of  acid 
reaction,  and  contains  about  33  gm.,  i.  e.,  2.2  per  cent,  of  urea; 
while  the  blood  from  which  it  is  derived  is  alkaline  and  contains 
only  0.05  to  o.i  per  cent,  of  urea.  The  liquid  must,  therefore, 
undergo  striking  changes  in  its  passage  from  the  glomerular 
capillaries  to  the  ureter. 

We  might  review  very  briefly  the  functions  of  the  different 
parts  of  the  kidneys: 

The  Glomerulus. — While  there  seems  to  be  no  doubt  that  this 
acts  largely  as  a  mechanical  filter,  there  is  some  evidence  that 
its  cells  may,  in  addition,  select  and  secrete  certain  of  the  elements 
of  the  blood.  Brodie  believes  it  to  be  an  expulsor  organ,  capable 
of  expansion  and  contracton. 

The  Tubules. — That  the  tubules  have  the  power  to  reabsorb 
water  and  some  of  its  dissolved  substances  is  apparent  from  a 
number  of  experiments.  Cushny  showed  not  only  that  water  was 
absorbed,  but  that  there  was  a  differential  reabsorption  of  certain 
of  its  salts,  apparently  in  proportion  to  their  diff  usability,  e.  g., 
sodium  chloride  more  readily  than  sodium  sulphate.  He  found 
also  that  in  marked  diuresis  the  proportion  of  these  salts  in  the 
urine  was  more  nearly  equal;  and  he  figured  that  reabsorption 
failed  to  take  place  because  of  the  rapidity  of  the  passage  of  the 
liquid  through  the  tubules.  Moreover,  destruction  of  the  tubule 
cells  experimentally  or  by  disease  is  regularly  followed  by  increase 
of  urine  excretion. 

That  the  tubules  have  also  a  specific  secretory  power  is  sug- 
gested by  the  results  of  the  injection  of  sodium  sulphindigotate 
into  the  blood.  Within  a  minute  or  two  the  urine  secreted  is  blue, 
showing  that  the  pigment  passes  out  in  the  urine.  If  the  kidney 
is  at  once  removed  and  the  coloring-matter  fixed  by  perfusion 
with  alcohol,  microscopic  examination  shows  the  tubule  cells 
deeply  stained  with  blue,  while  the  glomeruli  are  not  stained  at 
all.  This  suggests  that  the  pigment  has  passed  through  the 
tubule  cells  (presumably  was  excreted)  rather  than  through  those 
of  the  glomerular  capillaries.  Again,  if  the  blood-pressure  is 
reduced  below  40  mm.  mercury  (below  which  pressure  all  urine 
flow  ceases),  the  cortex  alone  is  blue,  and  the  pigment  is  found 
deposited  in  granules  in  the  striated  epithelial  cells  and  the  lumen 
of  the  first  and  second  convoluted  tubules.  After  the  injection 
of  uric  acid  in  a  solution  of  piperazin  Starling  found  uric  acid  in  the 
cells  and  lumen  of  the  convoluted  tubules.  Nussbaum's  experi- 
ment on  the  reno-portal  vein  of  the  frog  and  some  experiments  on 
poisoned  kidneys  also  point  to  a  specific  secretory  power. 

By  injecting  acid  indicators  into  the  blood  it  may  be  shown 
that  the  glomerular  fluid  is  alkaline,  and  that  the  urine  becomes 


452  PHARMACOLOGY   AND   THERAPEUTICS 

acid  in  the  convoluted  tubules ;  if  it  is  hurried  through  the  tubules 
by  active  diuresis,  it  is  less  acid  and  may  be  alkaline. 

Without  entering  further  into  the  theories  of  kidney  action, 
which  are  not  yet  soundly  established,  and  can  be  read  up  in  any 
recent  book  on  physiology,  we  will  assume  that  the  function  of  tlte 
glomerulus  is  to  pass  from  the  blood  to  the  uriniferous  tubules 
large  quantities  of  an  alkaline  fluid  which  contains  urea,  chlorides, 
phosphates,  sulphates,  and  under  some  circumstances  sugar  and 
other  substances,  in  the  proportion  in  which  they  occur  in  the 
blood.  And  that  the  functions  of  the  tubules  are:  (i)  To  change 
the  reaction  of  the  glomerular  fluid  to  acid.  (2)  To  add  to  it  cer- 
tain substances  by  excretion,  such  as  urea,  uric  acid,  creatinin, 
urinary  pigment,  phosphates,  and,  under  certain  circumstances, 
water.  (3)  To  concentrate  the  urine,  by  the  reabsorption  of  much 
of  its  water  and  of  some  of  its  dissolved  substances.  These  are 
reabsorbed  somewhat  according  to  their  absorption  power,  i.  e., 
sodium  chloride  readily,  sulphates  less  readily,  and  urea  not  at  all. 
But  it  has  been  demonstrated  that  the  excretion  of  various  sub- 
stances reaches  its  maximum  at  different  times  and  not  necessarily 
when  diuresis  is  greatest. 

As  the  function  of  the  kidneys  is  in  large  measure  to  keep  the 
blood  of  normal  composition,  even  minute  quantities  of  foreign 
substances,  such  as  potassium  iodide,  or  excessive  quantities  of 
normal  constituents,  such  as  sodium  chloride  and  sodium  bi- 
carbonate, may  be  rapidly  excreted  without  any  apparent  re- 
absorption. 

The  urine  is,  therefore,  made  up  essentially  of — (i)  water, 
(2)  such  dissolved  substances  as  have  been  removed  from  the 
blood  in  the  glomeruli  and  have  escaped  reabsorption,  and  (3) 
the  substances  excreted  by  the  tubule  cells.  Either  its  quantity 
or  its  quality  may  be  changed  by  an  alteration — (i)  in  the  con- 
stituents of  the  blood;  (2)  in  the  nitration  or  secretory  power  of 
the  glomeruli;  (3)  in  the  secretory  power  of  the  tubules;  or  (4)  in 
the  reabsorptive  power  of  the  tubules;  but  in  the  production  of 
diuresis  we  are  not  always  certain  which  of  these  are  the  factors 
involved. 

On  account  of  these  complex  factors  we  must  not  forget,  in 
treating  patients,  that  the  volume  of  the  urine  is  made  up  of 
water,  and  that,  therefore,  the  quantity  of  urine  excretion  is  not 
necessarily  a  measure  of  the  cxcrementitious  materials  that  are  being 
removed  from  the  body.  Indeed,  von  Noorden  states  that  a  con- 
centrated urine  may  carry  out  just  as  much  deleterious  matter  as 
one  less  concentrated.  As  the  normal  powers  of  healthy  kidneys 
are  vastly  more  than  sufficient  to  maintain  a  proper  blood  com- 
position, our  endeavor  in  disease  must  be  to  restore  the  kidney 


DIURETICS  453 

functions  or  to  minimize  the  amount  of  kidney  activity  required. 
We  have  no  proof  that  the  removal  of  edema  by  diuresis  benefits 
the  kidneys  themselves,  however  much  it  may  benefit  the  patient. 
We  cannot  confer  upon  the  kidneys  any  abnormal  powers,  or 
functions  new  to  kidney  tissue. 

Walker  and  Dawson,  Christian,  and  others  have  shown  that 
the  life  of  rabbits  with  severe  acute  experimental  nephritis  may 
be  definitely  shortened  by  the  repeated  administration  of 
diuretics,  at  least  those  of  the  caffeine  series,  and  potassium 
acetate.  Their  experiments  would  suggest  that  diuretics  are 
contraindicated  in  acute  nephritis,  but  the  success  of  diuretic 
methods  in  mercuric  bichloride  poisoning  points  otherwise. 
Christian  says  that  following  an  active  diuresis  there  may 
be  for  a  day  or  two  a  decrease  in  renal  function  as  measured 
by  the  index  of  urea  excretion.  This  is  probably  due  to  renal 
fatigue  and  not  to  renal  damage. 

The  Therapeutic  Production  of  Diuresis. — From  these  re- 
marks it  will  be  seen  that  the  site  of  the  diuresis  may  be  the 
glomerulus  or  the  tubule,  or  both;  and  that  diuresis  may  be 
brought  about  by: 

I.  Measures  which  increase  the  glomerular  fluid. 

(a)  By  increasing  the  blood-flow  through  the  kidney. 

(b)  By  lowering  the  osmotic  pressure  of  the  blood. 
II.  Measures  which  increase  the  tubular  secretion. 

III.  Measures  which  decrease  the  tubular  reabsorption. 

I.  Measures  Which  Increase  the  Glomerular  Fluid. — (a)  By 
Increasing  the  Blood-flow  Through  the  Kidney. — It  is  evident  that 
constant  replacement  of  the  blood  of  the  kidneys  must  take  place 
or  the  urine  will  cease  to  flow.  It  is  evident,  also,  that  glomerular 
filtration  is  dependent  upon  the  maintenance  of  a  certain  capil- 
lary pressure,  for  experiments  show  that  when  general  arterial 
pressure  falls  below  about  40  mm.  of  mercury,  the  urine  ceases 
to  flow.  The  capillary  pressure  in  the  glomerulus  is  maintained 
by  the  general  arterial  pressure,  by  the  small  size  of  the  efferent 
vessel  of  the  glomerulus  as  compared  with  its  afferent  vessel,  and 
by  the  friction  of  the  second  set  of  capillaries.  About  the  pressure 
in  the  efferent  vessel,  and  about  its  dilatation  and  contraction, 
we  know  nothing;  but  it  is  found  by  experiment  that  even  a 
moderate  resistance  to  the  venous  outflow  from  the  kidney  checks 
the  flow  of  urine.  We  know  at  present,  therefore,  that  the  flow 
of  urine  is  readily  influenced  by  changes  in  the  amount  of  blood  ~ 
passing  through  the  kidneys;  and  that  this  amount  of  blood  is  j 
regulated  by  the  general  arterial  pressure,  by  the  caliber  of 
the  kidney  arterioles,  by  the  back  pressure  in  the  kidney  - 
veins,  and  by  the  viscosity  of  the  blood.  Digitalis  is  one  of 


454  PHARMACOLOGY   AND   THERAPEUTICS 

the  best  of  diuretics  in  conditions  with  impaired  circulation. 
(See  Digitalis.) 

The  kidney  arterioles  are  the  sluice-gates  to  the  capillaries. 
If  general  arterial  pressure  remains  constant,  dilatation  of  the 
kidney  arterioles  allows  a  greater  blood-flow  through  the  kidney 
capillaries,  and  contraction  of  the  arterioles  determines  a  lesser 
blood-flow.  If  the  caliber  of  the  arterioles  remains  constant,  a 
rise  in  general  arterial  pressure  causes  more  blood  to  pass  through, 
and  a  fall  in  pressure  causes  less  blood  to  pass  through. 

It  is  a  general  rule  that  diuresis  is  accompanied  by  dilatation 
of  the  kidney  arterioles  through  a  local  action,  and  in  most  in- 
stances it  is  observed  that  diuresis  is  dependent  upon  such  dilata- 
tion. But  there  are  exceptional  instances  where  diuresis  has 
occurred  in  the  absence  of  dilatation  of  the  renal  arterioles, 
or  where  diuresis  has  failed  even  though  the  arterioles  were 
dilated. 

In  experimental  vascular  nephritis  Pearce  reports  dilatation 
of  the  vessels  from  caffeine  and  from  5  per  cent,  sodium  chloride, 
but  diuresis  from  the  caffeine  only.  Also,  if  the  kidney  is  pre- 
vented from  expanding,  i.  e.,  the  vessels  not  allowed  to  dilate, 
there  is  diuresis  from  caffeine,  but  not  from  various  diuretic  salts 
and  dextrose. 

(b)  By  Lowering  the  Osmotic  Pressure  of  the  Blood. — If  sodium 
chloride,  sodium  acetate,  urea,  or  dextrose  in  hypertonic  solution 
is  injected  into  the  blood,  the  osmotic  pressure  of  the  blood  is  at 
once  raised.  Fluid  passes  to  it  from  the  tissues,  the  blood  swells 
up,  and  a  condition  of  hydremic  plethora  with  lowered  osmotic 
pressure  is  brought  about,  i.  e.,  the  quantity  of  blood  is  greater 
than  normal,  the  tissues  or  tissue  spaces  having  been  drawn  upon 
for  a  diluting  fluid.  If  an  isotonic  saline  solution  is  injected 
into  a  vein,  swallowed,  or  administered  by  rectum,  this  hydremic 
plethora  results  without  the  imbibition  of  fluid  from  the  tissues 
or  tissue  spaces. 

In  hydremic  plethora,  under  the  influence  of  the  slightly 
raised  arterial  pressure  and  the  lessened  viscosity  of  the  blood, 
this  swollen  volume  of  blood  tends  to  promote  rapid  blood-flow, 
and,  as  a  consequence,  to  favor  transudation  of  the  excess  of 
fluid  through  capillaries.  The  kidney  capillaries  are  the  ones  by 
which  the  body  gets  rid  of  excessive  fluid ;  therefore  if  the  kidneys 
are  functionating  properly,  there  is  diuresis,  and  the  excess  of 
water  with  certain  dissolved  materials  is  rapidly  got  rid  of. 

Hydremic  plethora  and  its  resulting  diuresis  may  be  the  con- 
sequence of  the  absorption  of  dropsical  fluid,  as  under  the  adminis- 
tration of  digitalis.  It  may  be  produced  intentionally  by  the 
ingestion  of  water,  or  of  solutions  of  dialyzable  substances. 


DIURETICS  455 

The  result  in  any  case  is  diuresis,  unless  the  molecular  concentra- 
tion of  the  plasma  is  decreased.  For  example,  a  hypotonic 
sodium  chloride  solution  intravenously,  because  of  its  low  salt 
content,  will  make  a  hydremia  without  diuresis  (Davis). 

Of  dialyzable  substances,  those  with  a  pronounced  diuretic 
action  are: 

(a)  Inorganic  Salts. — Sodium  sulphate,  sodium  chloride,  and 
sodium  or  potassium  bicarbonate,  but  the  only  ones  employed 
as  diuretics  are  the  bicarbonates. 

(6)  Organic  Salts. — The  acetates,  citrates,  and  tartrates, 
which  break  down  into  carbonates  in  the  blood.  They  are  po- 
tassium acetate,  potassium  citrate,  potassium  bitartrate,  potas- 
sium and  sodium  tartrate,  liquor  ammonii  acetatis,  and  liquor 
ferri  et  ammonii  acetatis  (Basham's  mixture).  The  best  of  these 
is  potassium  acetate.  (See  Imperial  Drink,  page  88,  and  A.  B.  C. 
mixture,  page  102.) 

(c)    Urea,     (d)  Dextrose. — (See  Glucose.) 

All  these  substances  tend  to  have  an  effect  upon  the  urination 
in  direct  proportion  to  the  osmotic  pressure  which  they  exert. 
In  hydremic  plethora,  if  the  kidneys  are  not  functionating  well, 
as  in  chronic  nephritis,  and  there  is  water  retention,  the  excess 
of  water  tends  to  transude  through  the  systemic  capillaries  and 
to  favor  the  production  of  edema  and  dropsy. 

Water. — Ordinary  drinking-water  is  hypotonic,  and  is  prac- 
tically unabsorbed  by  the  stomach.  But  it  imbibes  salts  from  the 
food  or  mucus,  or  from  the  superficial  cells  of  the  alimentary  tract, 
or  takes  up  the  sodium  chloride  which  is  formed  in  the  duodenum 
by  the  neutralization  of  the  hydrochloric  acid  of  the  gastric 
juice.  Hence  it  becomes  a  salt  solution,  and,  instead  of  passing 
on  through  the  intestine  to  the  rectum,  is  absorbed.  Therefore 
when  excess  of  water  is  ingested  the  excess  does  not  normally 
pass  out  with  the  feces;  and  under  ordinary  conditions  of  absorp- 
tion, no  matter  how  much  is  drunk,  does  not  produce  a  movement 
of  the  bowels  (Starling).  So  the  ingestion  of  large  quantities 
of  water  leads  to  a  condition  of  hydremic  plethora,  which  results 
in  increased  urination.  Water  in  large  amounts  is,  therefore, 
diuretic,  and  in  its  elimination  tends  to  carry  out  certain  dis- 
solved substances,  especially  urea,  sulphates,  and  phosphates. 
Leonard  Hill  says  it  only  washes  out  the  urea  stored  in  the  tissues 
and  does  not  provoke  increased  destruction  of  tissue  protein; 
but  Hawk  has  gathered  some  evidence  that  copious  water  drink- 
ing results  not  only  in  a  removal  of  stored-up  urea,  but  also  in 
increased  protein  destruction. 

The  body  has  a  great  capacity  for  the  storing  of  water,  so  that 
even  when  the  excretory  apparatus  is  impaired,  excessive  amounts 


456  PHARMACOLOGY   AND   THERAPEUTICS 

of  water  can  be  taken  for  many  days  before  dropsy  sets  in.  In 
these  cases  it  is  evident  that  a  diuretic  is  indicated  before  dropsy 
is  apparent.  But  water  should  not  be  given,  for  in  dropsical 
conditions  large  quantities  of  water  serve  only  to  increase  the 
already  "water-logged"  condition  of  the  patient. 

II.  Measures  Which  Increase  the  Tubular  Secretion,  and 
III.  Measures  Which  Decrease  the  Tubular  Absorption. — Be- 
tween these  two,  we  cannot  at  present  discriminate.  The 
diuretics  which  act  upon  the  tubules,  however,  may  be  divided 
for  practical  purposes  into — 

1.  Those  which  are  non-irritant  to  the  kidney,  and  conse- 
quently in  the  larger  doses  do  not  produce  inflammation — caffeine, 
theobromine,  theophylline,  diuretin,  agurin.     (See  Caffeine.) 

Caffeine  itself,  because  of  its  dominant  other  effects,  is  little 
employed  as  a  diuretic,  but  the  action  of  the  series  is  obtained  by 
theobromine  and  theophylline  (theocine)  and  their  soluble 
combinations.  Usually  in  conditions  with  undiseased  kidneys, 
as  in  the  edema  of  cardiac  insufficiency,  and  less  often  in  kidney 
cases,  they  are  effective  diuretics,  and  the  author  has  in  several 
instances  seen  the  urine  flow  for  twenty-four  hours  reach  200  to 
300  ounces  (6  to  9  liters)  after  two  or  three  doses  of  20  grains  of 
theophylline  or  theobromine  sodio-salicylate.  In  one  dropsy  case 
at  the  City  Hospital  the  drug  was  continued  for  seven  days  with 
a  high  daily  urine  output  and  a  total  loss  of  60  pounds  in  the 
patient's  weight.  However,  because  of  their  tendency  to  cause 
renal  fatigue,  Christian  recommends  that  they  be  given  in  full 
dosage  for  a  period  of  two  or  three  days  only,  followed  by  a  similar 
period  without  any  diuretic.  Both  drugs  are  irritating  to  the 
stomach,  theophylline  being  more  so  than  theobromine;  and  in 
such  case  their  soluble  compounds  in  5  per  cent,  solution  may  be 
given  intravenously. 

In  acute  and  chronic  nephritis  the  indication  for  the  use  of 
these  drugs  is  not  so  clear  as  in  the  cardiac  cases;  indeed,  with 
theophylline  in  renal  cases  Christian  found  that  kidney  efficiency 
as  judged  by  the  index  of  urea  excretion  was  more  often  decreased 
by  their  use  than  increased,  and  with  caffeine  even  in  normal 
persons  Benedict  noted  a  degree  of  nitrogen  retention.  In  a  case 
of  kidney  disease  at  St.  Luke's  the  urine  rose  to  300  ounces  (9 
liters)  the  first  day,  and  remained  high  for  the  seven  days 
during  which  the  drug  was  administered  (see  Caffeine). 

2.  Those  which  are  irritant,  and  in  overdose  may  produce 
inflammation.     They  are: 

((/)  Volatile  oils,  and  resinous  or  aromatic  drugs,  especially 
the  oils  of  sandalwood,  juniper,  turpentine,  the  balsam  of  copaiba, 
and  the  drugs  buchu,  cubeb,  kava-kava,  matico,  uva  ursi,  and 


DIURETICS  457 

cantharis.     These  are  less  prescribed  as  diuretics  than  as  urinary 
antiseptics.     The  oil  of  jumper  is  present  in  "gin." 

(b)  Certain  drugs  which  contain  irritant  glucosides  and  are 
mostly  used  in  the  form  of  infusion;  for  example,  scoparius  or 
broom,    which    contains    scoparin,    asparagus,   which    contains 
asparagin,  and  triticum,  which  contains  triticin. 

(c)  Calomel. — A  dose  of  calomel  at  the  beginning  of  diuretic 
treatment  will  often  hasten,  or  at  least  appear  to  hasten,  the  on- 
set of  diuresis.     This  is  particularly  true  in  venous  stagnation.    It 
may  act  by  irritating  the  kidney  cells;  but  its  action  is  more 
probably  due,  not  to  direct  diuresis,  but  to  the  relief  of  the  kidneys 
through  the  removal  of  fluid  by  the  bowels. 

To  compare  the  various  diuretics,  Raphael  (1894)  placed  him- 
self on  a  uniform  diet  for  a  long  period,  the  daily  allowance  of 
fluid  being  1 180  c.c.  His  twenty-four-hour  urine  ranged  between 
750  and  960  c.c.  When,  in  addition  to  his  uniform  diet,  he  took 
diuretics,  his  urine  increased  as  follows: 

INCREASE. 

0.4  gm.  oil  of  turpentine 1 1  per  cent. 

0.2  gm.  oil  of  juniper  +  1000  c.c.  water in 

0.5  gm.  caffeine  and  sodium  salicylate 42 

0.5  gm.  theobromine  and  sodium  salicylate  (diuretin)  2 

1.5  gm.  theobromine  and  sodium  salicylate 14 

3.0  gm.  theobromine  and  sodium  salicylate 53 

30.0  gm.  sugar  of  milk 34 

1000.0  c.c.  water 100 

1000.0  c.c.  carbonic  water 73 

1000.0  c.c.  beer 100 

1000.0  c.c.  claret 80 

1000.0  c.c.  milk 153 

As  a  general  rule,  the  following  things  are  true  about  diuresis: 

1.  The  filtered  substances,  urea  and  salts,  are  increased  in 
proportionally  greater  amount  than  the  secreted  substances,  uric 
acid,  creatinin,  pigment,  etc.,  and  there  may  be  no  increase  in  the 
latter  substances  at  all.     The  excretion  of  phosphates  is  increased 
by  water  (Hawk),  and  that  of  uric  acid  by  atophan. 

2.  Substances  which  are  ordinarily  partially  reabsorbed  are 
passed  out  in  greater  proportion  to  the  other  substances  than 
normally,  their  proportional  reabsorption  being  prevented  either 
by  the  more  rapid  flow  which  takes  place  through  the  tubules,  or 
by  impairment  of  the  reabsorbing  power  of  the  cells. 

3.  Frequently  for  the  first  day  or  two  of  diuresis  there  is  a 
great  increase  in  the  amount  of  some  of  the  solids  excreted,  as  if 
there  had  been  accumulation  of  these  in  the  body  and  they  were 
being  washed  out.     Magnus  says  that  for  each  salt  (substance) 
there  is  a  "secretion  threshold,"  a  certain  degree  of  concentra- 
tion in  the  blood,  above  which  an  increase  leads  to  the  elimina- 


458 


PHARMACOLOGY  AND   THERAPEUTICS 


Fig.  57. — Drawing  made  to  scale  from  tracings  taken  from  a  dog  by  C.  C.  Lieb. 
Horizontal  line  of  figures,  time  in  minutes.  Black  line,  arterial  pressure;  dotted 
line,  urine  flow.  The  close  relation  between  general  blood-pressure  and  urine  flow 
is  striking.  The  drugs,  in  the  order  used,  with  dose  per  kilo,  are:  Caffeine,  2  mg., 
urine  little  affected.  Theophylline  acet-sodium,  3  mg.,  urine  much  increased. 
Spirit  of  nitroglyccrin,  0.3  c.c.,  urine  decreased.  Thcobromine  sodium  salicylate, 
3  mg.,  urine  increased.  Caffeine  and  sodium  benzoate,  4  mg.,  continues  theo- 
bromine  effect.  Animal  bled,  20  c.c.  per  kilo,  great  fall  in  urine.  Saline  infusion, 
25  c.c.  per  kilo,  great  increase.  Camphor  in  oil,  20  mg.,  decided  fall.  Pituitary 
extract,  o.i  c.c.,  fall  followed  by  rise.  Epincphrine  solution,  o.i  c.c.,  fall  followed  by 
rise.  Tincture  of  caniharides  was  then  given  in  amounts  large  enough  to  produce 
inflammation  of  the  kidney. 


DIURETICS  459 

tion  of  the  excess  with  an  increased  secretion  of  water.  It  may  be 
that  in  diuresis  the  level  of  this  "secretion  threshold"  is  lowered. 
By  atophan,  for  example,  it  is  possible  to  reduce  the  uric  acid  of 
the  blood  away  below  normal. 

4.  Without  abundant  supply  of  water  there  is  no  diuresis. 

5.  The  continued  use  of  diuretics  results  in  fatigue  of  the 
kidney  cells. 

Therapeutics  of  Diuresis. — The  two  great  uses  of  diuresis  are 
— (i)  To  promote  the  elimination  of  toxins,  usually  of  bacterial 
or  metabolic  origin,  and  (2)  to  cause  the  removal  of  dropsy.  In 
the  first  case  copious  amounts  of  water  must  be  administered  to 
serve  as  the  medium  of  excretion;  in  the  second,  the  ingestion  of 
water  is  kept  below  normal.  When  the  human  kidneys  are  im- 
paired, as  in  nephritis,  there  may  be  abnormal  retention  of  various 
substances,  i.  e.,  the  kidney  loses  its  power  to  excrete  to  the  full 
degree.  Such  substances  may  be  water,  chlorides,  urea,  creatinin, 
uric  acid,  etc.  In  such  cases  the  application  of  this  or  that 
diuretic  is  purely  experimental. 

1.  To  promote  the  elimination  of  toxins. — Assuming  that  the 
kidneys  are  functionally  good,  diuresis  brought  about  in  any 
manner  tends  to  increase  the  excretion  of  any  dialyzable  substance 
in  the  blood;  for  the  water  in  passing  out  must  carry  with  it  some 
of  each  of  the  filterable  substances  of  the  blood.    If  the  poisons 
are  not  filterable,  they  pass  out  in  the  urine  only  if  the  tubule  cells, 
or  perhaps  the  cells  of  the  glomeruli,  can  take  them  from  the  blood 
and  excrete  them.     The  tubules  are  exceedingly  sensitive  to 
foreign  substances  in  the  blood,  and  are  probably  competent  to 
excrete  many  of  the  unusual  deleterious  substances  of  the  body, 
such  as  toxins  of  disease  or  abnormal  products  of  metabolism; 
but  we  have  no  satisfactory  data  to  indicate  just  how  much  of  a 
role  they  do  play  in  such  elimination.     To  promote  the  elimina- 
tion of  drug  poisons,  such  as  strychnine,  a  saline  infusion  or  2 
per  cent,  sodium  sulphate  intravenously  may  be  administered. 
For  metallic  poisons  see  the  Lambert-Patterson  treatment  for 
mercuric  bichloride  poisoning.      This  is  also  a  method  for  over- 
coming suppression  of  the  urine  in  acute  kidney  cases. 

By  promoting  absorption  of  tissue  fluid,  diuresis  may  have 
an  additional  value  by  getting  the  tissue  toxins  into  the  blood 
stream  to  be  excreted. 

2.  To  cause  the  removal  of  dropsy  and  edema — i.  e.,  the  removal 
of  fluid  from  the  potential  tissue  spaces.     The  treatment  of  drop- 
sical or  edematous  conditions  is  of  the  greatest  interest  from  a 
diuretic  point  of  view.     There  are  four  great  causes  of  edema,  viz., 
venous  engorgement  from  cardiac  disease,  kidney  impermeability, 
tissue  retention,  and  abnormal  general  capillary  permeability. 


460  PHARMACOLOGY   AND   THERAPEUTICS 

As  a  rule,  a  combination  of  diuretics  is  advised,  and  a  diminution 
of  the  water  intake. 

(a)  Venous  engorgement  has  been  discussed  at  length  under 
Digitalis.     At  times  the  best  results  are  obtained  with  digitalis  to 
activate  the  circulation,  and  diuretin  or  a  saline  such  as  potassium 
acetate  to  activate  the  kidney  or  dilate  the  kidney  arterioles. 

(b)  Kidney  impermeability  is  a  difficult  thing  to  overcome, 
because  it  depends  on  kidney  disease.     The  impermeability  for 
salts,  urea,  uric  acid,  water,  etc.,  may  depend  largely  on  the  type 
of  affection  of  the  kidney.     Much  experimental  work  has  been 
done  on  forms  of  acute  nephritis  produced  by  poisons.     Thus 
poisons  affecting  the  tubular  epithelium  are  uranium  nitrate, 
mercuric  chloride,  and  the  alkaline  chromates;  poisons  affecting 
the  glomerular  capillaries  are  arsenous  acid,  cantharidin,  and  rat- 
tlesnake venom ;  and  a  poison  that  will  affect  both  capillaries  and 
tubules  is  diphtheria  toxin.     The  glomerular  capillaries  seem  to 
be  affected  beyond  all  other  capillaries,  probably  by  a  remote  local 
action  in  the  elimination  of  the  poisons. 

In  the  experimental  acute  tubular  nephritis  there  is  copious 
urination,  increased  by  most  diuretics.  In  the  experimental  acute 
glomerular  nephritis  there  is  no  polyuria  and  deficient  response  to 
diuretics.  In  either  case,  after  a  few  days'  exposure  to  the  poison, 
the  lesions  tend  to  extend  and  become  combined;  but  when  the 
poison  is  stopped,  the  kidneys  heal  and  do  not  show  the  lesions  of 
chronic  nephritis  (Pearce). 

In  acute  or  chronic  nephritis  with  edema  we  have  little  in- 
formation to  guide  us  in  our  choice  of  diuretics,  and  our  best 
plan  is  to  use  a  saline  diuretic  with  one  of  the  caffeine  series, 
such  as  theobromine  sodio-salicylate.  Because  of  the  danger  of 
producing  kidney  fatigue,  Christian  and  others  recommend 
large  closes  for  only  two  or  three  days  at  a  time.  Pearce 
has  shown  that  kidney  injury  alone  is  insufficient  to  cause 
edema.  There  must  be,  in  addition,  general  capillary  per- 
meability and  hydremic  plethora. 

(c)  Tissue  retention  of  water  as  a  cause  of  edema  is  a  subject 
not  fully  understood.     In  chronic  edematous  states  it  is  customary 
to  put  the  patient  on  a  diet  very  low  in  sodium  chloride,  the  so- 
called  "salt-free"  or  "salt-poor"  diet.     This  reduces  the  sodium 
chloride  in  the  urine,  but  seems  to  make  little  alteration  in  the 
percentage  of  sodium  chloride  in  the  blood-plasma.     It  is,  how- 
ever, an  effective  measure  in  many  cases.     The  author  has  seen 
cases  in  which  the  salt  had  been  so  reduced  that  diuresis  occurred 
only  after  the  administraton  of  sodium  chloride. 

(d)  Abnormal  permeability  of  the  capillaries  of  the  body  may 
result  from  poisons,  as  in  arsenic  and  food  poisoning  and  uremia. 


ANTIPYRETIC   DRUGS  461 

It  is  to  be  remembered  that  diuresis  requires  water  as  its 
medium,  so  that  to  promote  the  elimination  of  poisons  copious 
drafts  of  water  should  be  administered  with  the  diuretic.  If, 
however,  there  is  edema  or  any  degree  of  water  retention,  all 
fluids  should  be  restricted.  (See  also  Caffeine,  Theobromine,  and 
Theophyllin.) 

ANTIPYRETICS 

Antipyretics  are  remedies  which  tend  to  reduce  the  tempera- 
ture in  fever.  The  reduction  of  temperature  may  be  brought 
about  by  cold  or  by  drugs. 

Cold. — Some  of  the  methods  for  applying  cold  are  the  cold 
bath,  the  cold-pack,  and  the  drip  sheet;  and  for  local  use  the  cold 
compress,  the  ice-water  coil  or  ice-bag,  rectal  irrigation  with 
ice-water,  the  cold  spinal  douche,  etc. 

The  cold  bath  is  employed  in  typhoid  fever.  In  the  tub-bath 
the  patient  is  covered  with  a  sheet  and  lifted  into  a  bath  contain- 
ing water  at  about  70°  F.  The  primary  shock  is  less  if  he  is  placed 
in  the  bath  at  85°  or  90°  F.,  and  the  water  cooled  rapidly  to  70°  F. 
by  the  addition  of  ice.  The  head  should  be  cooled  with  ice-cold 
compresses,  and  the  body  rubbed  vigorously  during  the  bath.  A 
preliminary  dose  of  whisky  tends  to  dilate  the  cutaneous  vessels 
and  increase  the  output  of  heat.  The  bath  is  continued  for  from 
ten  to  fifteen  minutes.  The  bed-bath  is  made  by  having  the 
patient  on  a  large  piece  of  rubber  sheeting,  of  which  the  edges  are 
raised  over  pillows  or  rolled-up  sheets.  Cold  water  is  poured  in 
around  the  patient,  ice  added,  and  the  patient's  body  soused  with 
the  water  by  means  of  a  large  sponge. 

In  the  cold-pack  one  or  two  sheets  are  wrung  out  of  cold  water 
and  wrapped  around  the  patient,  the  first  layer  of  sheet  passing 
beneath  the  arms  and  being  tucked  between  the  legs.  The  patient 
lies  on  a  blanket,  in  which  he  is  then  completely  enveloped  up  to 
the  neck.  After  fifteen  minutes  these  coverings  are  removed.  If 
desired,  the  sheets  may  again  be  wrung  out  of  cold  water  and  the 
process  renewed.  When  the  drip-sheet  is  used  as  an  antipyretic 
measure  the  patient  is  wrapped  in  a  sheet  in  the  same  manner  as 
above,  but  sits  up  and  has  cold  water  poured  over  him.  These 
methods  of  applying  cold,  whether  followed  by  a  good  reaction 
or  by  shivering,  cause  an  increase  in  the  viscosity  of  the  blood 
(Determann,  Austrian). 

ANTIPYRETIC  DRUGS 

The  group  known  as  antipyretics  includes  only  those  drugs 
whose  most  pronounced  property  is  to  reduce  the  temperature 
of  fever.  It  does  not  include  aconite,  alcohol,  digitalis,  phenol, 


462  PHARMACOLOGY   AND   THERAPEUTICS 

and  other  drugs  which  possess  the  power  to  lower  temperature  in 
fever,  but  have  other  important  activities  that  lead  us  to  class 
them  elsewhere.  For  convenience,  the  essential  antipyretics  may 
be  divided  into  three  therapeutic  groups,  viz.,  the  analgesics,  the 
antimalarials,  and  the  antirheumatics. 

THE  ANALGESIC  ANTIPYRETICS 

The  official  ones  are  antipyrine,  acetanilid,  and  acet-phenet- 
idin.  Some  of  the  quinoline  derivatives,  among  the  so-called 
coal-tar  drugs,  have  been  employed  largely  as  antipyretics 
(kairin,  thallin,  etc.),  but  have  been  discarded  in  favor  of  more 
certain  remedies. 

Antipyrina,  antipyrine,  phenyl-dimethyl-pyrazolon, 

NCCH5 
CH3N/\CO 


CH3C 


CH 


is  freely  soluble  in  water  and  alcohol,  and  has  a  slightly  bitter 
taste.  It  is  a  body  closely  resembling  the  alkaloids,  and  is  pre- 
cipitated by  tannic  acid,  alkalies,  and  some  other  alkaloidal  pre- 
cipitants.  With  calomel  it  forms  a  poisonous  compound.  With 
spirit  of  nitrous  ether  or  other  nitrites  it  gives  a  deep-green  color 
(iso-nitroso-antipyrine) ;  with  ferric  salts  a  deep  red ;  with  chloral 
hydrate,  naphthol,  phenol,  and  sodium  salicylate  it  liquefies;  with 
caffeine,  quinine,  and  some  other  alkaloids  it  forms  soluble 
double  salts.  Dose,  4  grains  (0.25  gm.).  For  local  application  it 
is  employed  in  5  to  25  per  cent,  aqueous  solution.  Close  relatives 
are  pyramidon,  dimethyl-dimethyl-amino-pyrazolon,  and  sali- 
pyrine,  antipyrine  salicylate. 

Acetanilidum,  acetanilid,  phen-acetamide,  C6H5.NH.CH3CO, 
has  a  slightly  biting  taste,  ancl  is  soluble  in  190  parts  of  water  and 
in  3.4  of  alcohol.  Its  solubility  in  water  is  increased  by  acids  and 
decreased  by  alkalies.  Dose,  4  grains  (0.25  gm.). 

Close  relatives  of  acetanilid  are  exalginc,  methyl-acetanilid, 
and  salophen,  acetanilid-salicylic  acid. 

Acet-phenetidinum,  C6H4.OCoH5.NH.CH3CO,  more  familarly 
known  under  the  proprietary  name  "phenacetin,"  is  a  derivative 
of  phenol.  It  is  soluble  in  1310  parts  of  water  and  15  of  alcohol, 
and  is  almost  tasteless.  The  chemic  formula  shows  that  phen- 
acetin might  properly  be  called  oxyethyl-acetanilid,  but  it  is  not 
a  direct  derivative  of  acetanilid,  and  may  better  be  placed  in  a 
separate  group  with  other  phenetidin  compounds.  It  is  not 
readily  soluble  in  water.  Dose,  5  grains  (0.3  gm.).  The  other 


THE    ANALGESIC    ANTIPYRETICS  463 

phenetidin  compounds  worthy  of  note  are  lactophenin,  a  lactic- 
acid  derivative;  malakin,  a  salicylic-acid  derivative;  and  apolysin 
and  citrophen,  the  mono-  and  tri-phenetidin  citric  acids. 

Pharmacologic  Action. — These  drugs  all  reduce  temperature 
in  the  same  way,  are  all  analgesic,  are  all  nerve  sedatives,  and  are 
all  antiseptic.  This  antiseptic  action  is  mild,  but  is  the  same  in 
kind  as  that  of  the  phenol  group  of  antiseptics,  to  which  they  are 
closely  related  chemically.  Their  antipyretic  action  is  powerful, 
as  exhibited  in  the  reduction  of  temperature  in  the  infectious 
fevers.  Their  analgesic  action  is  chiefly  shown  in  headache  and 
nerve  and  muscle  pains. 

Locally,  antipyrine  differs  from  the  others  in  that  a  10  to  25 
per  cent,  solution  applied  to  a  mucous  membrane  acts  mildly  like 
cocaine,  inducing  vasoconstriction  with  shrinkage  of  the  mem- 
brane and  the  checking  of  small  hemorrhages,  and  lessening  pain. 
Acetanilid  is  slightly  irritant  locally,  and  phenacetin  is  bland. 

The  Antipyretic  Effect.- — It  seems  probable  that  in  many  cases 
hyperthermy  or  fever  is  a  protective  reaction  on  the  part  of  the 
body,  and  in  these  cases  moderate  degrees  of  fever  require  no 
antipyretic  treatment.  There  are  some  cases,  however,  in  which 
even  mild  degrees  of  fever  seem  disadvantageous,  and  others  in 
which  the  protective  fever  reaction  overshoots  the  mark  and  pro- 
duces a  high  and  dangerous  body  temperature,  and  it  is  in  these 
that  antipyretic  measures  are  indicated.  Hektoen  believes  that 
fever  is  an  indication  that  foreign  protein  is  being  broken  down. 

In  fever  the  temperature  may  be  reduced  either  by  lessened 
production  of  heat  or  by  increased  output  of  heat,  or  by  both. 
The  tendency  of  the  body  is  to  keep  itself  at  a  normal  tempera- 
ture. If  the  body  is  too  warm,  there  is  a  dilatation  of  cutaneous 
blood-vessels  and  an  outpouring  of  sweat,  so  that  the  body  will 
undergo  heat  loss  by — (i)  Radiation  and  convection  of  heat,  more 
heated  blood  from  the  interior  being  brought  to  the  surface ;  and 
(2)  the  evaporation  of  sweat.  At  the  same  time  there  is  a 
tendency  to  lessened  muscular  activity  with  diminished  heat 
production.  This  combination  of  lessened  heat  production  and 
greater  heat  dissipation  tends  to  bring  the  overheated  body  to  a 
normal  temperature. 

If,  on  the  contrary,  the  body  is  too  cool,  there  is  stimulus  to 
greater  muscular  activity,  the  muscular  act  of  shivering  takes 
place,  sweating  stops,  and  the  cutaneous  vessels  are  contracted. 
So  there  are  greater  heat  production  and  lessened  heat  dissipa- 
tion, and  the  too  cool  body  becomes  warmed. 

This  heat  production  and  heat-dissipation  are,  to  a  certain 
extent,  under  the  control  of  some  central  structures  spoken  of 
collectively  as  the  heat-regulating  centers,  the  function  of  which 


464  PHARMACOLOGY   AND   THERAPEUTICS 

is  to  keep  the  body  temperature  normal.  There  are  probably 
thermogenic  centers  governing  the  production  of  heat,  and 
thermolytic  centers  governing  the  dissipation  of  heat,  and  it  is 
believed  that  they  are  situated  in  the  corpus  striatum  and  optic 
thalamus.  Barbour  and  Wing  have  shown  that  heat  applied 
directly  in  these  regions  results  in  body  cooling,  and  cold  results 
in  body  warming.  Any  variations  from  the  normal  affect  these 
centers;  and  they  at  once  send  out  impulses  which  influence  the 
mechanisms  for  the  production  or  the  dissipation  of  heat,  as  may 
be  needed. 

In  active  muscular  exercise  much  heat  is  produced;  but 
through  the  heat-regulating  mechanism  heat  dissipation  is  in- 
creased to  correspond,  so  that  the  temperature  scarcely  rises,  and 
if  it  does,  is  soon  restored  to  normal.  The  extra  loss  of  heat 
is  brought  about  by  dilatation  of  the  cutaneous  vessels  and 
sweating. 

But  in  some  of  the  infectious  fevers  that  have  been  studied 
the  heat  production  has  been  found  very  little  increased,  and 
the  hyperthermy  to  be  due  to  the  failure  of  the  heat-dissipating 
mechanisms  to  do  their  work.  For  example,  in  one  case  of  malaria 
Liebermeister  estimated  the  increase  in  heat  production  during 
the  hot  stage  to  be  21  to  24  per  cent.,  much  less  than  the  increase 
during  active  exercise;  but  during  the  malarial  chill,  owing  to  the 
muscular  activity  of  vigorous  shivering,  the  heat  production  rose 
147  per  cent.  At  the  same  time,  owing  to  the  constriction  of  the 
cutaneous  vessels,  the  mechanisms  for  heat  dissipation  were  in 
abeyance.  It  would  seem  in  such  cases  that  the  fever  results 
from  the  failure  of  the  heat-regulating  centers  to  make  the  heat 
loss  keep  pace  with  the  heat  production.  Whether  or  not  the 
toxins  of  the  disease  affect  the  center  directly  is  still  a  question. 

A  chill  is  considered  to  be  the  result  of  surface  cooling  from 
constriction  of  the  cutaneous  arterioles,  the  skin  being  the  site 
of  the  nerve-endings  through  which  temperature  changes  are 
perceived.  In  a  chill,  shivering  is  the  heat-producing  response  of 
the  regulators  to  the  cold  at  the  surface  rather  than  to  general 
body  temperature.  The  subsequent  fever  results  from  this 
excessive  heat  production  at  a  time  when  the  skin  vessels  are  still 
constricted  and  sweating  absent,  i.  c.,  when  heat  loss  is  at  a 
minimum. 

In  those  of  the  infectious  fevers  which  have  been  studied  in 
this  regard  there  is  a  great  increase  in  the  nitrogen  elimination 
during  the  fever,  but  no  material  increase  in  the  amount  of  fats 
and  carbohydrates  oxidized,  as  shown  by  the  elimination  of  CO2; 
therefore  heat  production  is  not  greatly  increased.  Just  the 
opposite  condition  is  found  in  active  exercise,  in  which  there  is 


THE    ANALGESIC   ANTIPYRETICS  465 

great  increase  in  the  elimination  of  CO2  and  only  a  moderate 
increase  in  the  nitrogen  of  the  urine. 

Liebermeister  has  likened  the  heat-regulating  centers  to  the 
heat-regulator  of  a  room.  The  heat  regulator  is  set  at  a  certain 
temperature;  if  the  room  gets  warmer,  the  mercury  rises  or  a 
metallic  band  expands,  and  by  making  an  electric  connection 
operates  on  one  or  more  dampers  in  the  furnace  so  that  the  fire 
burns  less  briskly,  or  shuts  down  the  registers  so  that  the  room 
receives  less  heat.  If  the  temperature  of  the  room  falls  below  that 
at  which  the  regulator  is  set,  the  dampers  or  registers  are  opened 
and  more  heat  comes  into  the  room.  Now,  to  carry  out  the 
analogy,  the  heat-regulating  centers  in  the  human  body  may  be 
thought  of  as  being  normally  set  for  a  temperature  between  98° 
and  99°  F.  If  the  temperature  goes  up  a  degree  or  two,  the  centers 
send  out  impulses  which  result  either  in  a  lessening  of  heat  pro- 
duction, i.  e.,  by  diminution  in  muscular  and  circulatory  activity, 
or  an  increase  in  heat  loss,  i.  e.,  by  dilatation  of  the  cutaneous 
vessels  and  sweating.  On  the  contrary,  if  the  temperature  falls 
a  degree  or  two,  the  heat  production  may  be  increased  by 
muscular  activity,  shivering,  etc.,  or  the  heat  loss  diminished  by 
contraction  of  the  cutaneous  vessels  and  the  stoppage  of  sweating. 

The  temperature-regulating  centers  have  little  discriminating 
po\ver,  and  a  surface  chill  may  induce  the  centers  to  constrict  the 
vessels  and  lessen  heat  loss,  and  at  the  same  time  to  increase  the 
production  of  heat,  so  that  fever  may  result.  To  what  extent  the 
body  reaction  which  results  in  fever  is  beneficial  or  harmful,  we 
are  not  yet  able  to  state.  Recently  certain  infections  seem  to  have 
been  cured  by  the  repeated  artificial  production  of  a  chill  with 
high  fever,  as  by  the  intravenous  administration  of  foreign 
protein,  usually  typhoid  vaccine. 

In  some  fevers  the  regulating  centers  may  lose  their  control  at 
certain  times  of  the  day  only.  In  tuberculosis  there  is  a  tendency 
to  afternoon  fever,  accompanied  by  headache,  discomfort,  and 
weakness  from  failure  of  heat  loss,  while  at  night  there  may  be  an 
overaction  of  the  mechanism  for  cooling,  with  diminished  metabo- 
lism and  the  production  of  profuse  sweat,  the  result  being  chilling 
of  the  surface  (cold  night-sweats)  and  a  fall  of  temperature 
to  subnormal.  Frequently,  in  tuberculosis  fever  cases,  the 
morning  temperature  is  normal  and  the  patient  feels  at  his  best 
at  that  time.  But  in  tuberculosis  the  centers  are  incompetent,  so 
that  a  slight  exertion  tends  to  produce  fever  at  any  time. 

In  malaria  there  is  a  severe  chill  with  contraction  of  the  skin 

vessels  and  the  generation  of  much  heat  (by  shivering).     After  a 

time  this  results  in  great  fever  and  discomfort,  the  contraction 

of  the  skin  vessels  and  the  absence  of  sweating  preventing  heat 

30 


466  PHARMACOLOGY   AND   THERAPEUTICS 

loss.  But  presently  the  centers  gain  control,  and  great  activity 
of  the  cooling  mechanism  follows.  The  result  is  dilatation  of  the 
skin  vessels  and  profuse  sweating,  with  a  fall  in  temperature 
to  normal  or  even  subnormal,  and  the  restoration  of  the  patient's 
comfort  till  the  next  chill  comes  on  a  day  or  two  later. 

In  a  continuous  fever  like  typhoid,  apparently  the  heat- 
regulating  centers  are  set  at  a  high  point,  102°  F.,  103°  F.,  104°  F. 
The  centers  are  just  as  sensitive  to  changes  as  ordinarily,  for 
shivering  follows  a  drop  of  2  or  3  degrees  in  the  temperature,  and 
sweating  results  from  a  rise  of  i  or  2  degrees.  But  the  tempera- 
ture at  which  the  centers  tend  to  keep  the  body  is  not  98.6°  F., 
but  102°  F.,  103°  F.,  or  104°  F.,  as  the  case  may  be. 

But  even  in  typhoid  fever  there  is  a  tendency  to  a  morning 
remission  of  temperature,  with  rise  to  the  highest  point  in  the 
afternoon  or  evening.  And  it  would  seem  as  if,  preceding  the  rise 
in  temperature  in  these  cases,  the  heat  regulators  are  affected  by 
the  poisons  of  the  disease,  so  that  they  allow  the  temperature  to 
rise  above  normal;  but  that,  at  a  certain  point,  the  centers  gather 
themselves  together  and  are  able  to  assert  themselves  and  regain 
their  control,  and  the  temperature  is  brought  backjx>ward  normal. 
This  makes  a  daily  rhythm. 

Action  of  Drugs. — A  drug  may  tend  to  lessen  the  temperature 
in  fever  by  decreasing  metabolism,  as  quinine,  by  lessening  the 
activity  of  the  circulation,  as  veratrum,  by  dilating  the  cutaneous 
vessels,  as  whisky,  or  by  inducing  perspiration,  as  solution  of 
ammonium  acetate.  But  antipyrine,  acetanilid,  acet-phenetidin, 
and  their  allies  act  centrally,  and  they  result  in  a  lowering  of  the 
temperature  in  fever  either  by  increasing  the  resistance  of  the 
regulating  centers  to  the  disease  poisons,  or  by  lowering  the  degree 
at  which  the  heat-regulating  centers  are  set  (if  we  may  use  such  an 
analogy).  Meyer  regards  them  as  mild  narcotics  to  irritated 
thermogenic  centers.  The  effect  of  these  drugs  is  not  to  any 
extent  to  reduce  heat  production,  for  they  do  not  diminish 
metabolism,  and  acetanilid  even  increases  metabolism.  They 
act  by  enabling  the  center  to  improve  its  control  over  the  mechanisms 
of  heat  dissipation,  which  are  the  ones  at  fault  in  the  infectious 
fevers. 

That  they  act  through  the  centers  is  shown  by  their  failure  to 
affect  the  temperature  in  health,  by  their  failure  to  reduce  tem- 
perature if  the  spinal  cord  is  severed,  and  by  the  fact  that  there 
is  no  attempt  on  the  part  of  the  body,  as  the  temperature  falls, 
to  manufacture  more  heat  by  shivering,  etc.,  as  occurs  when  the 
temperature  is  reduced  by  external  cold  (cold  baths,  etc.).  The 
lowering  of  temperature  by  these  drugs  may  be  accompanied  by 
profuse  sweating,  but  this  is  a  result  of  the  action  upon  the  centers, 


Fig.  58.— Acetanilid,  0.4  mg.  per  kilo.  Ventricle  (upper  tracing)  shows  increased 
lonicity  and  diminished  contractility  (down-stroke,  systole).  Arterial  pressure, 
lower  tracing,  falls  from  75  to  42  mm.  The  pulse-rate  drops  from  130  to  120. 
(Tracing  made  by  Dr.  C.  C.  Lieb.) 


Fig.  59. — Urticarial  eruption  following  antipyrinc  (\V.  S.  Gottheil  in  Archives  of 

Diagnosis). 


Fig.  60. —  Kxfoiiative  dermatitis    following   the   administration   of    large   doses  ot 


antipvrme.     JIair  and  nails  shed  (Schamberg). 


THE   ANALGESIC  ANTIPYRETICS  467 

and  they  are  still  antipyretic  if  the  sweating  is  prevented  by 
atropine.  Occasionally,  as  the  result  of  their  action,  the  centers 
reassert  themselves  too  strongly,  overshoot  the  mark,  and  carry 
the  temperature  away  below  the  normal.  In  some  cases  this 
results  in  collapse. 

Schutze  has  shown  that  antipyrine  does  not  prevent  the  forma- 
tion of  antitoxins  in  the  body,  so  it  does  not  interfere  with  the 
natural  forces  of  protection  against  disease,  except  as  fever  is 
beneficial. 

The  other  parts  of  the  nervous  system  are  also  affected  prac- 
tically alike  by  these  three  drugs. 

Cerebrum. — This  is  somewhat  depressed,  all  three  remedies 
being  useful  in  overcoming  nervous  irritability  and  restlessness. 
They  have  also  a  notable  power  in  lessening  pain,  especially  that 
from  neuralgia  or  neuritis,  or  a  lesion  of  the  central  nervous 
system.  They  are  especially  useful  in  headache.  Head  suggests 
the  hypothesis  that  the  analgesia  is  the  result  of  an  action  on 
synapses  in  the  pain-conveying  tract  in  the  thalamus  adjacent  to 
the  heat  center.  Stekel  believes  that  the  action  in  headache  is 
due  to  the  regulation  of  the  balance  between  heat  production  and 
heat  loss.  In  migrainal  headache,  for  example,  he  noted  that 
there  was  diminished  surface  temperature,  as  noted  in  the  axilla, 
though  normal  rectal  temperature,  and  that  after  small  doses  of 
antipyrine  the  axillary  temperature  rose  as  much  as  one  degree 
with  the  disappearance  of  the  headache.  Martin,  Grace,  and 
McGuire  found  a  marked  lowering  of  general  electrocutaneous 
sensitiveness  within  one  hour  of  mouth  doses  of  acet-phenetidin, 
5  to  15  grains  (0.3-1  gm.). 

These  remedies  are  not  strongly  hypnotic,  and  do  not  pro- 
duce somnolence  if  the  patient  is  up  and  about;  yet  if  taken  at 
bedtime,  they  favor  the  onset  and  maintenance  of  normal  sleep. 
The  cerebral  cortex,  then,  is  partly  depressed ;  yet  even  large  doses 
seem  to  have  very  little  depressing  effect  on  the  intellectual 
functions.  This  distinguishes  them  markedly  from  morphine, 
the  bromides,  and  other  central  depressants.  Phenacetin,  being 
an  ethyl  compound,  is  more  hypnotic  than  the  others;  antipyrine 
is  the  least  hypnotic.  But  antipyrine  is  said  to  be  more  depress- 
ing to  the  motor  areas,  so  that  it  has  been  used  in  epilepsy,  chorea, 
and  whooping-cough  with  more  or  less  benefit. 

The  centers  of  the  medulla  are  scarcely,  if  at  all,  affected.  In 
poisoning,  convulsions  may  occur,  clue  probably  to  stimulation 
of  the  spinal  cord  centers,  or  perhaps  to  asphyxia. 

Circulation. — A  number  of  cases  of  collapse  following  the  use 
of  antipyrine,  acet-phenetidin,  and  acetanilid  have  been  reported, 
so  that  these  drugs  have  acquired  a  bad  reputation  as  circulatory 


468  PHARMACOLOGY   AND   THERAPEUTICS 

depressants.  In  experimental  work  the  heart  muscle  is  directly 
stimulated  by  ordinary  doses,  the  beat  being  stronger  and  more 
rapid.  But  from  large  doses  the  muscle  is  weakened,  and  the 
beat  may  be  slow  and  irregular,  causing  collapse.  The  skin 
vessels  are  dilated  in  fever,  apparently  as  a  result  of  the  action  of 
the  heat-regulating  centers. 

The  collapse  action  is  most  pronounced  with  acetanilid,  and 
when  it  occurs  from  moderate  doses,  would  seem  to  be  due  to 
idiosyncrasy.  Nearly  all  the  fatalities  or  cases  of  serious  collapse 
from  these  drugs  have  come  from  very  large  doses  taken  in  the 
form  of  proprietary  headache  and  anti-pain  remedies.  Many  of 
these  cases  have  occurred  from  preparations  containing  caffeine, 
which  is  often  added  as  a  heart  stimulant,  and  it  has  been  shown 
by  Worth  Hale  that  they  are  more  dangerous  with  caffeine  than 
without,  and  less  dangerous  with  sodium  bicarbonate.  Employed 
in  proper  dosage,  these  drugs  are  practically  as  safe  as  any  other 
powerful  depressants,  but  must  be  used  with  equal  caution. 


Acetanilid, 
NaHCO, . . , 


Acetanilid. . | 
Acetanilid, 
caffeine, 
NaHCO. . .  | 

Acetanilid, 
caffeine  . . . .  I 


Fig.  61. — Toxicity  of  acetanilid  increased  strikingly  by  caffeine,  decreased  by 
sodium  bicarbonate.  Experiments  on  mice  by  Worth  Hale.  The  degree  of 
toxicity  is  represented  by  the  length  of  the  bars. 

Metabolism. — Antipyrine  and  acet-phenetidin  have  probably 
no  appreciable  effect  on  the  metabolism  in  health,  as  shown  by  the 
elimination  of  N,  the  absorption  of  O2,  and  the  elimination  of 
CO->.  Acetanilid  increases  metabolism,  as  shown  by  an  increase 
in  the  urea  and  total  nitrogen  of  the  urine. 

In  fever,  in  association  with  the  reduction  of  the  temperature, 
the  metabolism  is  lessened. 

Excretion  is  by  the  kidneys.  Antipyrine  appears  n  the  urine 
either  unchanged  or  as  oxyantipyrine  in  combination  with  glycu- 
ronic  and  sulphuric  acids.  Acetanilid  appears  as  para-amidophe- 
nol.  Acet-phenetidin  appears  as  phenetidin  compounds. 

Untoward  Effects. — From  idiosyncrasy,  antipyrine  not  infre- 
quently has  produced  a  scarlatiniform  rash  with  edema  of  the 
face  and  fever;  or  urticaria,  or  a  vesicular,  bullous,  or  eczematous 
eruption.  The  chief  untoward  effects  from  acetanilid  and  acet- 
phenetidin  are  cyanosis  and  collapse;  a  petechial  eruption  has 
been  noted  from  acet-phenetidin. 

Toxicology. — Acute  poisoning  shows  in  affections  of  the  alimcn- 


THE'  ANALGESIC   ANTIPYRETICS  469 

tary  tract  and  nervous  system.  There  are:  burning  and  swelling 
of  the  whole  alimentary  tract,  with  stomatitis,  nausea,  vomiting, 
gastritis,  perhaps  enteritis,  mental  dulness,  tremors,  convulsions 
(cerebral),  and  coma.  Death  results  from  failure  of  the  respira- 
tion. With  acetanilid  and  acet-phenetidin  cyanosis  and  collapse 
may  occur  early.  Toxic  effects  in  a  girl  of  twenty  have  been 
reported  from  10  grains  of  antipyrine.  The  treatment  is  by 
demulcents  for  the  gastro-intestinal  tract,  and,  if  necessary,  meas- 
ures to  combat  collapse. 

A  common  result  of  poisoning  by  acetanilid  and  acet-phenet- 
idin is  a  marked  cyanosis,  with  which  there  may  be  more  or  less 
dyspnea,  rapid  heart,  and  even  collapse.  There  is  some  destruc- 
tion of  red  cells,  and  some  formation  of  methemoglobin  by  reduc- 
tion, but  the  cyanosis  seems  to  be  out  of  proportion  to  the  meth- 
emoglobin formation  and  out  of  proportion  to  the  patient's 
symptoms.  There  is  probably  some  other  reduction  compound 
present  in  the  blood,  and  Bachmann  says  that  it  is  aniline.  Ten 
grains  of  acetanilid  taken  internally  have  produced  cyanosis, 
also  acetanilid  powder  applied  to  ulcer  of  the  leg.  The  author 
saw  one  case  from  a  phenacetin  powder,  probably  10  grains, 
given  by  a  pharmacist  for  headache. 

Chronic  Poisoning. — Many  nervous  patients  have  the  habit 
of  taking  these  drugs.  The  habit  does  not  have  a  hold  upon 
them,  like  the  morphine  habit,  and  can  be  broken  without  any 
systemic  rebellion;  yet  it  is  a  difficult  habit  to  overcome,  for  the 
symptoms  are  never  startling,  and  the  friends,  not  perceiving  any 
harm  from  the  drug,  note  the  apparent  suffering  when  the  drug  is 
stopped  (headache,  irritability,  restlessness,  sleeplessness).  There 
is  a  proneness  to  digestive  disturbances,  to  neuroses,  to  neuralgic 
pains,  to  various  skin  rashes,  as  erythema  and  eczema,  or  simple 
itching  without  a  rash,  and  to  mild  forms  of  neuritis.  There  may 
be  dyspnea  on  exertion,  and  other  evidences  of  cardiac  weakness. 
Impotence  has  been  reported.  We  have  had  under  our  care  one 
striking  case  of  chronic  poisoning  with  cyanosis  which  persisted 
for  weeks  after  the  stoppage  of  the  acetanilid.  Many  chemic 
and  spectroscopic  tests  of  the  blood  revealed  no  foreign  chem- 
ical other  than  methemoglobin.  Antipyrine  does  not  have  this 
effect  upon  the  blood. 

Therapeutics. — Antipyrine,  in  10  to  25  per  cent,  solution,  is 
employed  locally  to  stop  nasal  hemorrhage,  and  as  an  application 
in  the  painful  throat  of  tuberculous  laryngitis.  Systemically,  it 
has  been  used  with  moderate  success  as  a  motor  depressant  and 
general  sedative  in  cl/orca  and  whooping-cough.  It  has  also  some 
employment  in  diabetes  insipidus  and  diabetes  meUitus.  Its  other 
uses  are  those  of  acetanilid  and  acet-phenetidin. 


470  PHARMACOLOGY   AND   THERAPEUTICS 

All  the  drugs  of  the  group  are  employed  very  largely  for  their 
effects  upon  the  nervous  system  and  in  fever.  Their  general 
therapeutic  powers  are: 

(a)  To  overcome  fever.     In  the  high  temperature  of  influenza, 
tonsillitis,  etc.,  these  drugs  not  merely  reduce  the  temperature, 
but  also  greatly  promote  the  comfort  of  the  patient  by  lessening 
pain,  if  present,  by  lessening  nervousness  and  headache,  and  by 
promoting  quiet  and  rest.     There  are  cases  of  typhoid  fever  in 
which  these  antipyretics  have  a  decidedly  better  effect  than  the 
cold  bath,   as  when  there  are  shivering  and  cyanosis  during 
the  bath  and  for  some  time  afterward,  and  discomfort  both 
physically  from  the  cold  and  mentally  from  the  dread  of  the  next 
bath.     The  drugs  are  much  used  where  cold  baths  are  not  prac- 
ticable, and  their  antipyretic  and  quieting  effects  usually  last 
from  four  to  eight  hours.     In  the  afternoon  fevers  of  tuberculosis, 
also,  they  promote  the  comfort  of  the  patient. 

(b)  To  relieve  pain  in  conditions  without  fever ,  as  in  dysmenor- 
rhea  and  muscular  rheumatism;  headache,  migraine,  neuralgia, 
sciatica,  peripheral  neuritis;  the  lightning  pains  of  locomotor 
ataxia,  and  the  pain  of  an  intracranial  or  spinal  tumor.     They 
have  little  influence  on  pain  from  traumatism. 

(c)  To  allay  nervous  excitability  and  promote  sleep  in  conditions 
without  fever — emotional  shock,  hysteria,  and  nervous  conditions 
in  general. 

Administration. — Usually  in  capsules  or  tablets.  If  they 
cause  too  much  perspiration,  atropine  may  be  added. 

THE  ANTI-MALARIAL  ANTIPYRETICS 

CINCHONA 

There  are  two  medicinal  varieties  of  cinchona,  one  the  bark 
of  several  species  of  calisaya,  and  known  officially  as  Cinchona, 
the  other  the  bark  of  the  red  cinchona,  known  as  " Peruvian 
bark,"  and  with  the  official  title,  Cinchona  rubra.  These  are 
natives  of  South  America,  but  many  species  are  cultivated  in 
various  tropical  countries. 

Constituents. — There  are  about  19  alkaloids,  the  important 
ones  being  quinine,  cinchonine,  quinidinc,  and  cinchonidine.  In 
addition  there  are  quinic,  quinovic,  and  tannic  acids.  Red  bark 
contains  more  tannic  acid  and  less  quinine  than  calisaya,  but  both 
are  required  to  contain  5  per  cent,  of  total  alkaloid. 

Preparations  and  Doses. — Fluidextract  (calisaya);  dose,  15 
minims  (i  c.c.).  Tincture,  20  per  cent,  (calisaya) ;  dose,  30  minims 
(2  c.c.)-  Compound  tincture  (tinctura  cinchona;  composita),  10 


CINCHONA  471 

per  cent,  red  bark  with  serpentaria  and  bitter  orange  peel;  dose, 

i  dram  (4  c.c.). 

The  alkaloidal  salts,  dose,  5  grains  (0.3  gm.),  are: 
Quinine  sulphate,  (CzoHziNaOa^-HaSCX,  soluble  in  725  parts 
of  water  and  107  of  alcohol.  It  is  readily  soluble 
in  dilute  hydrochloric,  sulphuric,  or  phosphoric  acids, 
as  it  forms  the  soluble  double  salts,  or  in  the  case  of 
sulphuric  acid,  the  soluble  bisulphate.  Quinine  bi- 
sulphate,  C2oH24N2O2.H2S04,  soluble  in  9  parts  of  water 
and  23  of  alcohol.  Quinine  hydrobromide,  soluble  in  40 
parts  of  water  and  0.9  of  alcohol.  Quinine  hydrochloride, 
soluble  in  18  parts  of  water  and  0.8  of  alcohol.  Quinine 
dihydrochloride,  soluble  in  0.6  part  of  water  and  12  parts 
of  alcohol.  Quinine  and  urea  hydrochloride,  soluble  in  0.9 
part  of  water  and  2.4  parts  of  alcohol.  Quinine  salicylate 
and  quinine  tannate,  very  slightly  soluble  salts.  Cincho- 
nine  sulphate,  soluble  in  60  parts  of  water  and  12.5  of 
alcohol.  Cinchonidine  sulphate,  soluble  in  65  parts  of 
water  and  90  of  alcohol. 

Euquinine,  not  official,  is  the  ethyl  carbonic  ester.  It  is 
insoluble  in  water  and  not  bitter.  Its  dose  is  twice  that 
of  the  official  quinine  salts. 

Tinctura  antiperiodica,  N.  F.  (Warburg's  tincture),  is 
a  bitter,  aromatic  laxative,  sedative  and  antimalarial 
"shot-gun"  prescription.  It  is  made  of  quinine  sulphate, 
aloes,  rhubarb,  angelica  seed,  elecampane,  saffron,  fennel, 
prepared  chalk,  gentian,  zedoary,  cubeb,  myrrh,  camphor, 
white  agaric,  opium,  black  pepper,  cinnamon,  ginger, 
alcohol,  and  water.  Each  ounce  contains  opium,  |  grain 
(0.008  gm.);  quinine  sulphate,  10  grains  (0.6  gm.),  and 
extract  of  aloes,  8  grains  (0.5  gm.).  The  dose  is  i  dram 
(4  c.c.).  Warburg's  tincture  without  aloes  (sine  aloe)  is 
the  same  with  the  omission  of  the  aloes. 
Pilula  antiperiodica,  N.  F..  and  Pilula  antiperiodica  sine 
aloe,  X.  F.,  represent  i  dram  (4  c.c.)  of  the  corresponding 
tinctures. 

Ethylhydrocupreine    hydrochloride,    a    proprietary    remedy 
with  the  name  optocJiin,  is  a  close  chemical  and  pharma- 
cologic  relative  of  quinine.     It  is  derived  from  the  al- 
kaloid cupreine  of  China  cuprea  bark  or  is  made  from 
hydroquinine.     It  is  fairly  soluble  in  water  and  alcohol. 
Pharmacologic  Action. — Quinine  is  a  protoplasm  poison. 
Microorganisms. — Quinine  is  strongly  antiseptic,  and  retards 

the  development  of  bacteria  and  yeasts.     In  very  dilute  solution 

(i  :  10,000)  its  first  tendency  is  to  stimulate  or  irritate  protoplasm; 


472  PHARMACOLOGY   AND   THERAPEUTICS 

but  the  stimulation  is  soon  followed  by  depression,  and  in  motile 
organisms,  especially  protozoa  (ameba,  paramecium)  and  ciliated 
cells,  all  motion  very  soon  ceases.  Strong  solutions  cause  instan- 
taneous cessation  of  movement  and  kill  the  organisms.  The 
spirochetes  of  relapsing  fever  are  more  resistant,  and  can  live  in 
a  solution  of  i  :  500.  (See  page  24.) 

It  is  an  interesting  fact  that  various  cells,  under  the  influence 
of  quinine,  will  undergo  asymmetric  cell  division,  e.  g.,  the  ova. 
In  certain  low  vertebrates,  as  the  salamander,  dilute  solutions  of 
quinine  applied  to  the  epithelium  will  produce  cells  of  atypical 
mitosis  like  those  of  cancer.  This  effect  is  produced  by  other  pro- 
toplasmic poisons,  such  as  chloral  and  cocaine  (Wilson). 

The  enzymes  seem  to  be  slightly  retarded,  but  are  not  nearly 
so  much  affected  as  the  living  organisms.  Of  the  digestive  fer- 
ments, ptyalin  and  diastase  are  little,  if  any,  affected,  and  pepsin 
and  trypsin  are  distinctly  retarded  in  their  activity.  Other  fer- 
ments, such  as  the  blood-coagulating  and  the  oxidizing,  are  re- 
tarded; and  it  is  said  that  quinine  will  prevent  blood  or  fresh  vege- 
tables from  giving  the  guaiac  test,  which  depends  on  oxidation. 

The  leukocytes,  which  resemble  amebae  so  closely,  are  affected 
in  the  same  way  as  ameba?.  With  i  part  of  quinine  in  4000  of 
blood  they  lose  their  ameboid  movements,  become  spheric,  die, 
and  soon  disintegrate.  In  the  intact  animal,  a  strong  solution 
prevents  the  emigration  of  leukocytes  and  their  gathering  to 
form  pus  at  the  site  of  inflammation.  And  while,  in  man,  such 
closes  as  can  be  administered  do  not  show  this  pronounced  effect, 
still  there  is  some  effect  upon  the  leukocytes,  for  their  number 
may  be  reduced  to  one-half  or  one-fourth  the  normal  (2000  to  4000 
per  cubic  millimeter  instead  of  8000),  the  polynuclears  being 
reduced  out  of  proportion  to  the  lymphocytes.  Roth  (1913)  found 
a  primary  slight  increase  in  the  lymphocytes,  which  after  several 
hours  changed  to  a  decrease.  In  a  dog  an  intravenous  dose 
markedly  contracted  the  spleen  and  caused  a  decided  decrease  in 
the  white  cells,  especially  of  the  polynuclears.  He  thought  the 
primary  rise  in  man  might  be  due  to  squeezing  out  the  splenic 
leukocytes  by  its  contraction.  These  are  notably  of  the  lympho- 
cyte type. 

Locally,  the  inorganic  salts  are  distinctly  irritant  to  raw  sur- 
faces and  mucous  membranes,  as  when  its  solutions  are  used  in  the 
rectum  or  hypodermatically.  After  a  hypodermatic  of  the  hydro- 
chloride  of  quinine  and  urea  there  soon  ensues  a  pronounced  local 
anesthesia  which  lasts  for  some  hours.  Quinine  is  said  to  stimu- 
late the  growth  of  hair,  and  is  an  ingredient  of  rum  and  quinine, 
eau  de  quinine,  and  other  mixtures  which  are  sold  as  hair-stimu- 
lants. 


CINCHONA  473 

Alimentary  Tract. — It  is  intensely  bitter,  and,  given  before 
meals,  acts  as  a  bitter  to  promote  appetite.  Large  doses  irritate 
the  stomach  and  may  cause  nausea  and  even  vomiting.  There  is 
slight  retardation  in  the  activity  of  pepsin  and  trypsin,  while  the 
other  digestive  ferments  are  probably  not  affected.  It  is  to  be 
borne  in  mind  that  quinine  sulphate,  the  alkaloidal  salt  almost 
universally  employed,  requires  an  acid  medium  for  its  solution; 
therefore  it  is- administered  after  meals. 

Quinine  is  said  to  retard  the  absorption  of  salts,  and  also 
probably  of  other  substances  (foods  and  medicines),  from  the 
stomach  (Sollmann). 

Absorption. — If  the  quinine  salt  goes  into  solution  it  is  rapidly 
absorbed  from  the  intestine  and  may  appear  in  the  urine  in  fifteen 
minutes.  If  the  stomach  is  not  acid,  the  quinine  may  not  dis- 
solve. 

Circulation. — In  ordinary  therapeutic  doses  there  is  probably 
a  slight  increase  in  the  rate  of  the  heart  and  a  tendency  to  a  rise 
in  the  blood-pressure  from  mild  stimulation  of  the  heart  muscle 
and  of  the  arterial  muscles.  The  arterial  action  is  a  peripheral 
one,  for  on  perfusing  an  isolated  viscus,  there  is  contraction  of 
the  arterioles,  followed  in  a  short  time  by  their  dilatation.  In 
large  doses  there  is  direct  depression  of  the  muscles  of  the  heart 
and  of  the  arteries,  with  slow  pulse  (which  occurs  after  atropine, 
so  is  due  to  muscular  depression),  and  a  fall  in  blood-pressure. 
From  ordinary  therapeutic  doses  the  effect  on  the  circulation  is 
negligible. 

The  blood  we  have  already  spoken  of.  Its  coagulability  is 
decreased  and  its  white  cells  are  lessened  in  number  and  probably 
also  in  activity.  In  bleeding  experiments  on  dogs,  de  Sandro 
(1911)  noted  that  dogs  given  quinine  recovered  their  hemoglobin 
and  red  cells  less  readily  than  those  without  quinine. 

Cerebrum. — It  has  the  same  tendency  as  the  other  antipy- 
retics, but  not  to  so  great  a  degree,  to  allay  the  pains  of  neuralgia 
and  those  associated  with  the  onset  of  influenza  and  other 
acute  illnesses.  Large  doses  produce  cinchonism,  spoken  of 
later. 

Medulla. — Affected  only  in  poisoning.  Then,  after  a  brief 
stimulation,  the  respiratory  center  is  depressed,  and  death  takes 
place  from  its  paralysis. 

Spinal  Cord. — In  the  frog  the  reflexes  are  increased.  In 
mammals  there  is  probably  no  effect. 

Peripheral  Nerves. — After  hypodermatic  administration  there 
is  a  slow  and  prolonged  abolition  of  sensation  at  the  site  of 
injection. 

The  Eye. — In  some  persons  there  have  been  marked  changes 


474  PHARMACOLOGY   AND   THERAPEUTICS 

in  the  sight  after  a  therapeutic  dose.  There  are  diminished  acute- 
ness  of  vision,  contraction  of  the  field  of  vision,  color-blindness, 
and  dilated  pupil. 

In  the  fundus  there  are  seen  irregular  contractions  of  the 
retinal  and  choroidal  arteries,  edema  and  anemia  of  the  retina, 
pallor  of  the  optic  discs,  thrombosis  of  the  central  vein,  and  in 
some  cases  atrophy  of  the  optic  nerve,  with  more  or  less  per- 
manent blindness,  the  patient  sometimes  appearing  to  see  through 
a  veil.  The  diminished  vision  is  known  as  "quinine  amblyopia." 
The  blindness  is  known  as  "quinine  amaurosis."  DeSchweinitz 
reports  a  case  of  temporary  blindness  after  12  grains  of  quinine 
sulphate,  though  usually  the  doses  have  been  large.  According 
to  this  author  the  contracted  field  of  vision  does  not  regain  its 
normal  limits;  but  Parker  (1912)  reported  the  case  of  a  man  who 
took  240  grains  (15  gm.)  by  mistake,  was  completely  blind  for  a 
time,  and  had  recovered  full  vision  in  three  and  one-third  months. 
Weeks  reports  cases  showing  permanence  of  arterial  contraction 
with  paleness  of  optic  discs  and  retinae. 

Ear. — The  deafness  and  ringing  in  the  ears  which  are  of  such 
frequent  occurrence  seem  to  be  due  mostly  to  congestion,  though 
arterial  contraction  and  anemia  of  the  middle  ear  and  labyrinth 
are  reported.  Such  congestion  has  been  found  in  animals  after 
large  doses.  If  the  quinine  administration  is  continued,  per- 
manent deafness  may  result  either  from  degenerative  changes  in 
the  spiral  ganglia  of  the  cochlea  or  from  a  chronic  otitis  media 
arising  from  the  continued  congestion. 

Muscle. — Striped  and  cardiac  muscles  are  stimulated  at  first, 
the  muscles  being  more  irritable  and  able  to  lift  a  greater  load; 
but  they  are  soon  fatigued,  and  their  total  work  amounts  to  less 
than  normal.  That  the  muscle  itself  is  the  part  affected  is  proved 
because  quinine  has  the  same  effect  after  curare.  (Curare  para- 
lyzes the  motor  nerve-endings  to  voluntary  muscle.)  Smooth 
muscle  is  not  so  surely  affected,  except  perhaps  the  spleen  and 
uterus,  and  perhaps  that  of  the  arteries. 

Immunity. — In  persons  susceptible  to  quinine  Boerner  ob- 
tained a  positive  von  Pirquet  reaction  in  fifteen  minutes  from 
solutions  of  i  :  10  to  i  :  1000.  In  other  persons  there  was  no 
reaction. 

Elimination. — It  appears  very  soon  in  the  urine  (fifteen  to 
thirty  minutes),  and  most  of  it  is  excreted  in  a  few  hours.  Traces 
may  be  detected  for  three  days  or  more.  From  30  to  go  per  cent, 
of  it  may  be  recovered  from  the  urine  unchanged,  and  some  is 
changed  to  di-hydroxyl  quinine.  A  small  amount  appears  in 
other  secretions.  Koldewijn  says  that  traces  appear  in  the  milk. 
Through  irritation  or  circulatory  changes  of  the  skin  there  may 


Fig.  62.— Purpuric  and  vesicular  eruption  from  quinine  (W.  S.  GoUheil  in  Archives 

of  Diagnosis). 


CINCHONA  475 

be  various  rashes,  notably  a  scarlatiniform  rash,  eczema,  urti- 
caria, and  erythema  with  itching.  So  frequent  are  skin  rashes 
from  quinine  that  a  rash  of  unusual  type  regularly  elicits  the 
physician's  question,  "Have  you  taken  quinine?" 

Kidneys. — Large  doses  of  quinine  irritate  the  kidneys  and 
cause  albuminuria  or  even  hemoglobinuria  or  hematuria.  After 
the  use  of  quinine  for  long  periods,  uroerythrin  may  be  a  cause  of 
red  urine. 

Uterus. — Uterine  contractions  seem  to  be  favored,  and  the 
drug  is  employed  in  labor  to  increase  the  force  of  the  contraction 
of  the  second  stage.  In  the  isolated  guinea-pig  uterus  Lieb 
found  that  a  solution  of  i  :  100,000  caused  an  immediate  increase 
in  the  rate  and  strength  of  the  contractions,  and  that  i  :  25,000 
caused  tetanic  spasm  and  rapid  death  of  the  organ.  From  doses 
of  8  to  15  grains  (0.5-1  gm.)  Maurer  obtained  a  distinct  ecbolic 
effect  in  nearly  all  cases  within  forty  minutes.  It  is  a  common 
belief  that  quinine  may  produce  abortion  in  a  pregnant  women, 
and  I  have  seen  several  cases  where  abortion  in  the  first  three 
months  followed,  though  it  may  not  have  been  caused  by,  its 
use  for  cold  or  for  malaria.  There  are  also  many  cases  of  preg- 
nancy where  abortion  has  not  followed  its  use. 

Metabolism  is  affected  by  very  small  doses,  even  doses  small 
enough  to  have  no  other  effect.  At  first  there  is  a  slight  increase 
in  the  nitrogenous  content  of  the  urine,  probably  due  to  increased 
leukocyte  destruction;  but  soon  there  is  a  marked  decrease,  and 
this  is  especially  noticeable  in  the  urea  and  uric  acid.  The  same 
amount  of  nitrogenous  food  may  be  absorbed,  but  less  is  con- 
sumed by  the  body,  so  there  is  a  storing-up  of  proteins.  Quinine 
has,  then,  just  the  opposite  effect  to  fever,  which  is  associated  with 
excessive  protein  destruction.  There  is  no  evidence  of  incomplete 
oxidation  of  the  nitrogenous  products. 

Temperature. — The  normal  oxidation  processes  are  changed 
very  little,  if  at  all,  the  O2  taken  in,  and  the  CO2  given  off,  being 
about  the  same.  Oxidation  is  usually  taken  as  a  criterion  of  the 
amount  of  heat  generated,  yet  there  is  less  heat  generated  after 
quinine,  presumably  owing  to  its  lessening  the  destruction  of 
proteins.  Quinine  lowers  the  temperature  in  fever  almost  en- 
tirely by  lessening  the  production  of  heat;  and  as  it  lowers  tem- 
perature after  division  of  the  spinal  cord,  it  does  not  exert  this 
action  through  the  heat-regulating  centers. 

Like  all  antipyretics,  it  acts  best  at  about  the  time  of  a  usual 
remission  of  temperature,  and  has  but  little  effect  in  health.  It 
is  not  so  powerful  a  reducer  of  temperature  as  acetanilid,  and  in 
a  continuous  fever  like  typhoid  has  very  little  effect.  As  an  anti- 
pyretic it  has  largely  been  supplanted  by  more  effective  drugs. 


476  PHARMACOLOGY   AND   THERAPEUTICS 

Untoward  Symptoms. — Cinchonism,  skin  eruptions,  gastric 
disturbances,  diarrhea,  and,  rarely,  hemoglobinuria.  In  cincho- 
nism  there  are  fulness  in  the  head  (headache),  ringing  in  the  ears, 
deafness,  dizziness,  and  mental  dulness;  and  there  may.be  im- 
paired vision,  muscular  weakness  with  uncertain  gait,  and  slow, 
rather  weak  pulse.  The  cerebral  symptoms  are  attributed  to 
circulatory  changes.  Sicard  reports  15  cases  of  sciatic  paralysis 
from  the  intragluteal  injection  in  soldiers. 

In  some  people  there  is  idiosyncrasy  to  very  small  doses,  and 
in  these  susceptible  people  the  addition  of  bromides  lessens  the 
tendency  to  cinchonism. 

Toxicology. — The  usual  manifestation  of  overdosage  is 
cinchonism  (just  described).  Very  large  doses  induce  gastro- 
intestinal disturbances,  mental  sluggishness,  disturbance  of  sight 
and  hearing,  slow,  ineffective  respiration,  slow,  weak  heart, 
muscular  weakness,  and  collapse.  One  ounce  (30  grams)  pro- 
duced only  confusion  and  noises  in  the  ears,  but  it  may  not  have 
been  absorbed.  Quill  reports  unconsciousness  and  severe  collapse 
five  minutes  after  the  taking  of  ^  ounce  (15  gm.)  in  solution.  Baer- 
mann  reports  death  after  two  doses  of  8  grains  (0.5  gm.).  Two 
drams  (8  gm.)  have  also  been  reported  as  causing  death.  Harts- 
horn had  a  case  with  burning,  swollen  face,  scarlatiniform  rash, 
and  fever.  The  author  had  a  patient  in  whom  the  administration 
of  quinine  on  different  occasions  was  followed  by  chilliness,  sweat- 
ing, vomiting,  and  diarrhea. 

The  treatment  is:  for  cinchonism,  bromides;  for  collapse,  the 
regular  treatment  for  collapse. 

Therapeutics. — Locally. — i.  Quinine  and  urea  hydrochloride 
in  solution  has  come  into  extensive  use  as  a  local  anesthetic. 
Hertzler,  Brewster,  and  Rodgers  consider  it  suitable  in  all  opera- 
tions which  can  ordinarily  be  done  under  cocaine.  They  use  0.25 
per  cent,  in  normal  saline,  and  have  determined  that  stronger  solu- 
tions retard  healing.  Many  operators  use  solutions  of  i  to  3  per 
cent,  strength.  To  lessen  shock  Crile  uses  it  in  major  operations 
to  anesthetize  the  field  of  operation  in  advance  of  cutting,  and 
so  abolish  all  afferent  impulses.  Quinine  bisulphate,  i  :  3000  to 
i  :  500,  has  also  been  used  as  a  local  anesthetic. 

2.  Both  of  these  salts  have  been  employed  as  disinfectants  in 
gonorrheal  urethritis,  vaginitis,  cystitis,  and  as  wet  dressings  for 
infected  wounds. 

3.  In  amebic  colitis,  and  for  pin-worms,  a  solution  of  quinine 
bisulphate  i  :  2000  to  i  :  500,  or  quinine  and  urea  hydrochloride, 
0.5  per  cent.,  may  be  employed  as  a  colon  irrigation. 

4.  In  exophthalmic  goiter  Watson  uses  i  to  4  c.c.  of  a  30  to  50 
per  cent,  quinine  and  urea  solution  for  injection  into  the  thyroid, 


CINCHONA  477 

repeating  the  dose  every  three  or  four  days  for  eight  to  fifteen 
times.  It  produces  connective-tissue  proliferation  with  destruc- 
tion of  thyroid  cells,  and  is  almost  painless. 

5.  In  hemorrhoids  a  similar  solution  is  injected  at  the  base  of 
the  pile,  or  5-grain  (0.3  gm.)  suppositories  inserted. 

6.  The  quinine  salts  have  frequently  been  added  to  hair 
tonics. 

Alimentary  Tract. — Its  sole  value  by  mouth  is  as  a  bitter,  and 
for  this  the  preferred  preparation  is  the  compound  tincture  of 
cinchona.  It  is  not  a  true  tonic,  for  it  tends  to  inhibit  the  pro- 
teolytic  enzymes,  to  irritate  the  stomach,  and  to  retard  absorption, 
and  does  not  have  any  good  effect  on  muscle  at  all. 

Systemically . — It  is  employed  to  reduce  the  pains  of  influenza, 
the  afternoon  fever  of  tuberculosis,  and  the  discomfort  of  a  cold.  In 
neuralgia  and  headache  it  is  analgesic,  and  may  also  act  by  lessen- 
ing the  nitrogenous  waste  products  which  are  sometimes  the 
cause  of  headache.  It  is  not  a  very  powerful  antipyretic  or 
analgesic.  In  the  paroxysms  of  acroparesthesia  Putman  con- 
siders it  almost  specific.  In  bacterial  infections,  c.  g.,  septicemia, 
it  would  seem  to  be  harmful  rather  than  helpful,  for  it  depresses 
vitality  and  checks  phagocytosis.  For  uterine  effect  it  is  employed 
in  menorrhagia  and  uterine  inertia.  Among  skin  diseases,  it  has 
been  recommended  internally  in  pemphigus,  exfoliative  der- 
matitis, and  pityriasis  rubra. 

In  pneumonia,  Solis- Cohen  uses  15  grains  (i  gm.)  of  quinine 
and  urea  hydrochloride  hypodermatically,  repeated  every  two  or 
three  hours  for  two,  three,  or  four  doses.  The  fever  disappears 
by  lysis  instead  of  by  crisis. 

In  malaria  it  is  practically  specific.  The  asexual  forms  are, 
as  a  rule,  vulnerable  to  quinine;  the  gametes  or  sexual  forms  are 
not,  but  in  the  human  body  die  naturally  in  a  few  weeks.  In 
tertian  or  quartan  malaria,  about  two  or  three  hours  after  a  large 
dose  of  quinine,  the  parasites  in  the  red  cells  can  be  seen  to  have 
lost  their  ameboid  motions,  and  they  soon  become  granular  and 
die.  The  quinine  acts  most  strongly  on  the  forms  just  breaking 
into  spores  and  on  the  free-swimming  organisms;  and  as  these  are 
present  in  the  blood  about  the  time  of  the  chill,  the  quinine,  on 
account  of  its  rapid  absorption  and  rapid  excretion,  is  best  given 
just  at  this  time.  Fifteen  grains  (i  gm.)  may  be  administered  just 
before,  during,  or  after  the  chill,  and  because  of  possible  develop- 
ment of  new  asexual  forms  from  gametes,  should  be  followed  by  5 
grains  three  times  a  clay  for  two  or  three  months.  In  malarial 
regions  quinine  is  taken  in  large  quantities  as  a  prophylactic. 
Craig  recommends  10  grains  (0.7  gm.)  every  fifth  night.  There 
is  much  evidence  to  show  that  it  does  reduce  the  number  of  cases 


478  PHARMACOLOGY   AND   THERAPEUTICS 

in  a  malarial  community,  and  does  not  seem  to  do  any  harm  to 
the  takers.  In  pernicious  malaria  the  quinine  and  urea  hydro- 
chloride  in  10  per  cent,  solution  has  been  employed  up  to  100 
grains  in  a  day,  but  recovery  from  this  condition  is  rare  in  any 
case.  Brewster  reports  the  intravenous  administration  in  perT 
nicious  malaria  of  100  grains  in  six  hours  without  untoward 
effects. 

In  Uackwater  fever,  which  is  believed  by  many  to  be  a  malarial 
manifestation,  Cardamitis  says  that  quinine  does  more  harm  than 
good.  He  cites  1347  cases  treated  by  quinine,  with  24.42  per  cent, 
of  deaths,  and  1134  treated  without  quinine,  with  7.32  per  cent, 
of  deaths.  The  Panama  Canal  Commission  advises  against  its 
use  during  an  attack  of  hemoglobinuria  unless  there  are  numerous 
malarial  parasites  in  the  blood. 

In  amebic  dysentery,  Major  Brooke  believes  30  grains  (2  gm.) 
a  day  to  be  as  effective  as  ipecac. 

As  a  postoperative  prophylactic  against  nausea,  vomiting, 
gas-pains,  backache,  and  thirst  Bonnot  recommends  10  grains 
(0.7  gm.)  of  the  hydrochloride  in  2  ounces  (60  c.c.)  of  water  by 
rectum  every  six  hours  for  four  to  six  doses.  The  effect  is 
enhanced  by  the  addition  of  sodium  bromide. 

Administration. — For  its  bitter  effect,  the  cinchona  prepara- 
tions are  employed,  diluted  with  water.  For  systemic  effect,  the 
quinine  salts  are  preferred. 

These  salts,  because  of  their  bitterness,  are  usually  given  in 
capsules  or  coated  pills.  The  sulphate  is  the  one  in  common  use, 
and  its  absorption  is  more  sure  and  more  rapid  if  it  is  given  in 
solution  with  a  dilute  mineral  acid,  as  sulphuric,  hydrochloric, 
phosphoric,  or  aromatic  sulphuric.  The  hydrochloride,  the  di- 
hydrochloride,  and  the  bisulphate  are  to  be  preferred,  as  they  are 
soluble  without  the  addition  of  acid.  For  hypodermatic  and 
intravenous  use  the  bimuriate  of  quinine  and  urea  is  employed. 
Quinine  is  thought  to  act  better  in  malaria  if  given  with  arsenic 
and  some  aromatic,  as  ginger  or  capsicum,  and  this  is  especially 
the  case  in  the  estivo-autumnal  variety,  in  chronic  or  relapsing 
malaria,  and  in  "gamete  carriers." 

For  children,  it  may  be  given  in  the  form  of  the  comparatively 
tasteless  (because  insoluble)  tannate,  made  into  tablets  with 
chocolate — the  so-called  "quinine  chocolates";  or  it  may  be 
mixed  with  fluidextract  of  licorice  (incompatible  with  acids),  or 
with  syrup  of  yerba  santa,  which  has  the  peculiar  property  of 
lessening  the  appreciation  of  bitter  taste.  As  it  takes  some  time 
for  the  action  on  the  taste-buds  to  develop,  the  yerba  santa  prob- 
ably lessens  the  bitterness  solely  by  forming  the  insoluble  tan- 
nate. 


ETHYLHYDROCUPREINE  479 

Lascoff  states  that  a  mixture  of  quinine  and  acetylsalicylic 
acid,  allowed  to  stand  for  some  time,  develops  a  poisonous 
substance  resembling  digitoxin  in  its  action. 

The  other  alkaloids,  quinidine,  cinchonine,  and  cinchonidine, 
act  in  malaria  like  quinine,  but  in  poisoning  cause  epileptiform 
convulsions.  They  have  no  advantages  over  quinine  and  are 
more  expensive. 

ETHYLHYDROCUPREINE 

Ethylhydrocupreine  has  actions  and  uses  similar  to  those  of 
quinine,  but  because  of  a  specific  bactericidal  effect  upon  all 
forms  of  the  pneumococcus  it  has  come  into  use  in  the  treatment 
of  pneumonia.  In  vitro  a  solution  of  as  little  as  i  :  10,000,000 
may  be  inhibitory  to  the  pneumococcus,  and  i  :  500,000  is 
bactericidal.  In  serum  this  activity  is  reduced  to  one-fifth  or 
one-tenth.  In  lobar  pneumonia  the  method  of  Moore  and 
Chesney  at  the  Rockefeller  Institute  is  to  administer  daily  by 
mouth  a  beginning  dose  of  "]\  grains  (0.5  gm.)  of  the  hydro- 
chloride,  followed  by  2\  grains  (0.15  gm.)  every  three  hours  till 
a  total  of  22\  grains  (1.5  gm.)  have  been  given  for  the  day.  It  is 
the  consensus  of  opinion^that  this  amount  should  not  be  exceeded. 
It  represents  about  0.024  g111-  Per  kilo  per  twenty-four  hours. 
They  found  that  with  this  dosage  "a  specific  pneumococcidal 
action  appears  in  the  blood  within  a  few  hours  and  can  be  main- 
tained more  or  less  constant  for  several  days."  It  has  been 
noted  that  pneumococci  not  destroyed  early  may  rapidly  acquire 
complete  resistance  to  the  drug.  The  "pure  alkaloid"  may  be 
given  intramuscularly  in  solution  in  oil. 

Locally,  in  pneumococcus  eye  infections,  as  in  ulcus  cornea 
serpens,  which  is  highly  destructive  to  the  sight,  the  drug  has  a 
decidedly  curative  effect  in  twenty-four  to  forty-eight  hours. 
It  is  used  in  i  per  cent,  solution  applied  for  half  a  minute  every 
hour  following  cleansing  with  boric  acid  solution.  There  is  a 
primary  pain  followed  soon  by  comparative  analgesia. 

Toxicology. — The  poisonous  symptoms  are  those  of  quinine, 
but  amaurosis  has  occurred  in  so  many  instances  from  therapeutic 
doses  that  this  is  especially  to  be  watched  for.  Adler  reports  one 
case  after  only  two  4-grain  (0.25  gm.)  doses.  At  the  Rockefeller 
Institute,  after  four  7^ -grain  (0.5  gm.)  closes  at  eight-hour  inter- 
vals, a  patient  was  unable  to  distinguish  light  for  six  days,  and 
at  the  end  of  five  months,  as  reported  by  Weeks,  had  slightly 
reduced  fields  of  vision  with  color  vision  very  indefinite,  many  of 
the  retinal  arteries  narrowed  and  their  walls  irregularly  thickened, 
and  optic  disks  and  retinae  pale. 


480  PHARMACOLOGY   AND   THERAPEUTICS 

ANTIRHEUMATIC  ANTIPYRETICS 
SALICYLIC   ACID 

Salicylic  acid  (acidum  salicylicum,  C6H4OH,COOH)  is  chemic- 
ally orthosalicylic  acid,  and  is  an  organic  acid  which  exists  natur- 
ally in  combination  in  the  volatile  oils  of  birch  and  wintergreen. 
It  is  generally  prepared  synthetically  from  phenol.  The  reputed 
superiority  of  salicylate  made  from  the  natural  oils  is  not  sub- 
stantiated by  the  experimental  work  of  Eggleston  and  others. 
Engelhardt  found  phenol  present  in  a  number  of  samples  of  both 
the  artificial  and  the  natural  oil.  Salicylic  acid  has  a  biting 
taste,  and  is  soluble  in  460  parts  of  water  and  in  2.7  parts  of 
alcohol.  The  salts  of  the  alkali  metals  are  readily  soluble  in 
water. 

Preparations  and  Doses. — Salicylic  acid;  dose,  y|  grains 
(0.5  gm.);  sodium  salicylate  and  strontium  salicylate;  dose,  15 
grains  (i  gm.). 

The  salicylates  of  ammonium,  quinine,  bismuth,  and  physos- 
tigmine  are  official,  but  in  the  available  dosage  do  not  give  a 
salicylic  action. 

Microorganisms. — In  a  solution  of  i  in  500  salicylic  acid  is  anti- 
septic, and  will  inhibit  or  retard  the  growth  of  bacteria,  yeasts, 
and  molds;  and  as  in  these  dilutions  it  is  not  corrosive  to  living 
tissue,  or  poisonous  to  human  beings,  except  in  large  amounts,  it 
is  safe  for  use  in  and  about  the  body.  But  because  it  is  not  readily 
soluble  in  water,  its  use  as  an  antiseptic  is  confined  largely  to  the 
preservation  of  foods,  the  treatment  of  parasitic  skin  diseases,  and 
the  preparation  of  a  mild  antiseptic  wash  known  as  "boro-sal." 
Leach  says  that  quantities  sufficient  to  preserve  milk  affect  the 
taste  of  the  milk.  It  belongs  to  the  phenol  group  of  antiseptics, 
but  does  not  possess  the  destructive  properties  and  the  penetrat- 
ing power  of  carbolic  acid,  and  it  retains  its  antiseptic  power  in 
fatty  and  alcoholic  preparations. 

The  alkaline  salicylates,  though  less  antiseptic  than  the  acid 
itself,  are  freely  soluble  in  water  and  are  used  in  the  preservation 
of  foods.  The  Hygienic  Laboratory  recommends  a  i  per  cent, 
solution  of  sodium  salicylate  as  a  fly-poison. 

Enzymes. — The  action  of  these  is  inhibited  or  retarded,  a  i  per 
cent,  solution  being  sufficient  to  stop  the  ptyalin  action  on  starch. 
Pepsin  is  somewhat  lessened  in  its  activity,  and  probably  also  the 
other  digestive  ferments.  Very  weak  solutions  seem  to  favor  fer- 
ment action. 

Local  Action. — Besides  its  antiseptic  action,  it  tends  to  stop 
local  sweating,  as  of  the  hands  or  feet;  to  soften  and  facilitate  the 


SALICYLIC  ACID  481 

removal  of  accumulations  of  horny  epithelium,  as  of  corns  or 
warts,  without  causing  inflammatory  changes  in  the  healthy 
underlying  tissues;  and  in  chronic  skin  diseases,  such  as  eczema, 
to  promote  the  growth  of  healthy  skin.  It  is  irritant  to  mucous 
membranes. 

Methyl  salicylate  and  the  volatile  oils  of  wintergreen  and 
birch  are  counterirritants. 

Alimentary  Tract. — Its  taste  is  biting,  and  it  is  locally  irritant. 
Its  tendency  is  to  retard  gastric  fermentation  and  the  action  of 
the  digestive  ferments.  Whether  or  not  it  can  reduce  intestinal 
putrefaction  is  a  question,  for  while  Strasburger  claims  that  the 
number  of  bacteria  in  the  feces  is  distinctly  reduced,  other 
observers  have  been  unable  to  detect  any  diminution  in  the 
indican  of  the  urine.  (See  Salol.)  By  large  quantities  the  pro- 
duction of  bile  is  increased,  but  the  use  of  the  drug  for  this  purpose 
in  therapeutics  has  not  been  shown  to  have  any  value. 

The  volatile  oil  salicylates  have  a  typical  carminative  action, 
and  in  moderate  dosage  are  well  borne;  the  other  salicylates  are 
irritant  and  frequently  produce  nausea  and  even  vomiting. 

Absorption  is  rapid  from  the  stomach  and  duodenum. 

Systemically,  it  resembles  acetanilid  in  its  analgesic  properties, 
but  is  much  milder.  It  increases  metabolism,  yet  is  antipyretic 
by  dilating  the  vessels  and  promoting  sweating,  and  so  increasing 
heat  loss.  Whether  there  is  an  effect  on  the  heat-regulating 
center  or  not  is  not  proved.  Mandel  found  that  it  would  prevent 
a  rise  of  temperature  from  xanthine. 

Giglio  found  salicylate  in  the  synovial  fluid  of  many  joints;  and 
Fillippi  and  Nesti  obtained  it  from  the  synovial  fluid  from  the  hip- 
joint  of  dogs  one  hour  after  its  administration  by  mouth.  It  was 
present  for  from  twenty-eight  to  fifty-four  hours.  They  found  it 
also  in  the  joints  of  acute  articular  rheumatism,  but  only  in  the 
merest  traces  in  a  gonorrheal  joint.  Hanzlik  and  his  co-workers 
find  the  percentage  in  joint  fluids  and  blood  practically  the  same, 
that  after  200  grains  (13  gm.)  in  both  rheumatics  and  non-rheu- 
matics being  about  0.025  Per  cent.  They  found  only  the  sodium 
salt  and  not  any  free  salicylic  acid.  Dixon  states  that  the  joint 
pain  and  stiffness  are  removed  by  the  injection  into  the  joint  of  a 
salicylate.  According  to  Falk  and  Tedesco  (1909),  it  appears  in 
all  inflammatory  exudates;  and  they  recommend  this  as  a  diagnos- 
tic point  in  sputum  examinations.  They  claim  that  the  sputum 
of  tuberculosis  and  pneumonia,  being  an  exudate,  gives  the  sali- 
cylic test,  while  the  sputum  of  bronchitis  and  bronchiectasis,  being 
a  secretion,  does  not  give  the  test.  Bastedo  and  Johnson  were 
unable  to  distinguish  by  this  test,  and  found  no  salicylate  in 
tuberculous  sputum. 
31 


482  PHARMACOLOGY   AND   THERAPEUTICS 

Except  for  the  dilatation  of  the  skin  arterioles,  which  is  pro- 
nounced, the  effect  upon  the  circulation  is  usually  negligible  in 
therapeutics.  The  tendency  of  moderate  doses  is  to  stimulate 
slightly  the  heart  muscle  and  the  vasoconstrictor  center;  that  of 
large  doses  is  to  depress  them.  In  the  blood  the  leukocytes  tend 
to  be  increased  in  number. 

Metabolism. — As  shown  by  the  rise  of  nitrogen,  phosphorus, 
and  sulphur  in  the  urine,  there  is  increased  protein  destruction. 
The  excretion  of  urea  and  uric  acid  are  increased,  the  rise  in  the 
latter  being  sometimes  as  much  as  50  per  cent.  Fine  and  Chace 
and  Denis  have  shown  a  marked  reduction  of  the  uric  acid  in  the 
blood,  Denis  attributing  this  to  a  lowered  threshold  of  the  kidney 
for  circulating  urates.  It  does  not  produce  an  acidosis  (Hanzlik). 

Excretion  is  by  the  kidneys,  chiefly  as  salicyluric  acid,  a 
glycocoll  compound  which  gives  a  violet-red  color  with  ferric 
chloride.  Traces  are  also  found  in  the  bile,  milk,  and  sweat.  The 
appearance  in  rheumatic  and  other  exudates  has  been  referred  to 
above.  In  rheumatism  there  seems  to  be  an  increased  destruc- 
tion. 

The  kidneys  may  be  irritated  by  large  quantities,  and  Hanzlik 
and  associates  have  shown  that,  both  in  rheumatics  and  non- 
rheumatics,  albumin,  leucocytes,  and  casts  appear  in  the  urine 
after  full  doses,  the  albuminuria  ceasing  when  the  salicyl  is 
excreted.  They  found  no  effect  on  the  phthalein  excretion  or  on 
the  blood  nitrogen.  But  among  drugs  of  this  class  salicylic  acid 
is  a  comparatively  safe  one,  for  quite  frequently  100  or  200  grains 
a  day  of  sodium  salicylate  have  been  given  without  signs  of 
kidney  inflammation. 

Toxicology. — The  early  signs  of  overdosage  are:  nausea,  vom- 
iting, and  sometimes  diarrhea;  or  headache,  ringing  in  the  ears, 
and  deafness;  or  mental  excitement.  As  judged  by  these  signs, 
Hanzlik  (1913)  found  that  for  human  adults  the  toxic  amount  of 
sodium  salicylate  is  about  200  grains  (13  gm.) ,  of  methyl  salicylate 
and  aspirin  about  120  grains  (8  gm.),  and  of  displosal,  100  grains 
(6.7  gm.). 

Salic ylism  resembles  cinchonism  and  is  characterized  by 
fulness  in  the  head,  headache,  mental  excitement  with  loquacity 
or  a  talkative  delirium,  or  mental  dulness  and  apathy,  with 
ringing  in  the  ears,  deafness,  disordered  vision,  and  muscular 
weakness.  The  ear  symptoms  are  not  so  common  as  from 
quinine,  and  arc  due  either  to  congestion  or  anemia  or  to  de- 
generation of  the  nerve-elements  of  the  cochlea.  Scheyer  reports 
a  case  of  labyrinthitis  with  permanent  impairment  of  the  hearing. 
I  he  eye  symptoms  are  also  associated  with  circulatory  changes  in 
the  retina  or  degenerative  changes  in  retina  or  optic  nerve. 


SALICYLIC   ACID  483 

In  the  salicylic  intoxication  the  cerebral  symptoms  may 
resemble  those  from  atropine,  producing  the  so-called  "salicylic 
jag."  The  patient  is  talkative  and  very  cheerful,  and  may  pass 
on  to  delirium  with  hallucinations,  motor  activity,  and  attempts 
to  get  out  of  bed.  The  cerebral  excitement  may  be  prevented, 
at  least  in  part,  by  bromides. 

Very  large  doses  produce  weakness  of  the  heart  and  depression 
of  the  respiratory  and  vasoconstrictor  centers,  with  collapse. 
But  the  writer  has  frequently  seen  20  grains  of  the  sodium  salic- 
ylate  given  every  two  hours,  and  occasionally  30  grains,  without 
any  noticeable  effect  on  the  heart's  action  or  the  blood-pressure. 
Occasionally,  through  idiosyncrasy,  even  small  doses  induce 
cardiac  weakness.  Seiler  reports  the  death  of  a  seven-year-old 
child  after  75  grains  (5  gm.),  Gubler  the  death  of  an  adult  after 
2\  drams  (10  gm.),  and  Goodhart  a  death  after  55  grains  (3.6  gm.) 
given  in  proper  therapeutic  doses.  Hanzlik  found  no  especial 
tolerance  for  the  salicylates  in  acute  rheumatism.  (Although 
phenol  and  salicylic  acid  are  closely  related  chemically,  neverthe- 
less they  cannot  be  considered  together  pharmacologically  or 
therapeutically.) 

Therapeutics. — Locally,  salicylic  acid  itself  is  employed: 

1.  As  a  surgical  antiseptic,  in  the  form  of  Thiersch's  solution 
or  boro-sal  (acid  salicylic,  2;  acid  boric,  8;  in  water,  1000). 

2.  In  sweating  of  feet  and  hands,  in  alcoholic  solution;  and  in 
bromidrosis  (smelly  feet),  mixed  with  boric  acid,  and  placed  dry 
in  the  shoes. 

3.  In  fungous   skin   diseases    (ringworm,   etc.)    and   chronic 
eczema,  in  ointment  form.     Lassar's  paste  (Pasta  Zinci,  N.  F.)  is 
composed  of  salicylic  acid,  2  parts,  zinc  oxide  and  starch,  of  each, 
24  parts,  and    petrolatum,  a  sufficient  quantity  to  make  100 
parts. 

4.  To  remove  corns  and  warts,  in  solution  in  flexible  collodion, 
15  grains  (i  gm.)  to  2  drams  (8  c.c.).     It  should  not  be  applied 
beyond  the  corn,  or  it  may  cause  the  adjacent  skin  to  peel. 

Internally,  the  sodium  salicylate  is  employed: 

1.  In  acute  articular  rheumatism  and  Us  complications — 10  to 
20  grains  (0.7-1.3  gm.)  every  two  or  three  hours.     That  the 
salicylates  give  prompt  relief  is  a  very  frequent  experience,  but 
there  is  some  evidence  that  they  do  not  diminish  the  length  of  the 
disease,  the  occurrence  of  endocarditis  or  the  frequency  of  relapse. 
Denis  suggests  that  their  value  may  be  due  to  the  promotion  of 
the  excretion  of  toxins.     The  writer  believes  in  their  specificity. 

2.  In   acute  tonsillitis,   pharyngitis,   groining  pains,   sciatica, 
lumbago,  muscular  rheumatism,  pleurisy,  etc.,  all  of  which  may 
have  a  true  rheumatic  origin.     Seibert  recommends  it  in  chorea, 


484  PHARMACOLOGY   AND   THERAPEUTICS 

but  most  men  find  it  useless  in  this  disease.  Cockayne  treated 
355  cases  with  60  to  300  grains  (2-20  gm.)  daily  without  influence 
on  the  course  of  the  chorea. 

3.  In  the  indefinite  muscular,  joint,  or  neuritic  pains,  which  are 
loosely  spoken  of  as  rheumatic. 

4.  In  gouty  attacks  it  is  as  valuable  as  atophan  (Fine  and 
Chace).    In  chronic  gout  and  chronic  rheumatism  it  is  analgesic, 
but  not  curative. 

5.  In  diabetes,  von  Noorden  (1912)  considers  it  the  most 
valuable  of  the  drugs  used,  except  the  nerve  sedatives  (codeine, 
etc.),  but  Hall  could  distinguish  no  desirable  effect.    (See  also 
Acetyl-salicylic  Acid  and  Salol.) 

Administration. — Sodium  salicylate  is  given  in  capsules  or 
cachets  with  plenty  of  water,  or  in  solution  in  wintergreen  water 
or  other  flavored  liquid.  Its  sweetish  taste  is  unpleasant  and 
nauseating  to  many.  An  alkaline  bromide  lessens  the  tendency 
to  salicylism,  and  sodium  bicarbonate  lessens  the  irritation  of  the 
stomach,  though  it  does  not  diminish  the  toxicity  or  the  irritant 
action  on  the  kidneys.  There  is  nothing  gained  by  enormous 
doses  of  sodium  bicarbonate,  as  recommended  by  Lees.  To 
avoid  too  great  toxic  effects  the  doses  should  be  divided  up  and 
given  at  frequent  intervals,  and  constipation  assiduously  avoided. 

Seibert  (1911)  has  suggested  the  hypodermatic  use,  recom- 
mending the  injection  of  to  c.c.  of  a  20  per  cent,  solution  for  each 
100  pounds  of  body  weight.  He  repeats  the  dose  every  twelve 
hours,  preceding  it  by  an  injection  of  a  weak  cocaine  solution 
because  of  the  pain.  Heyn  advocates  rectal  administration, 
the  beginning  dose  being  about  2  drams  (8  gm.)  with  4  to  6  ounces 
(120-180  c.c.)  of  water  or  starch-water.  It  appears  in  the  urine 
in  fifteen  to  thirty  minutes,  and  is  mostly  absorbed  in  twelve 
hours. 

It  has  also  been  used  intravenously  in  20  per  cent,  solution  in 
doses  of  20  grains  (1.3  gm.),  but  this  solution  causes  inflammation 
or  a  slough  if  it  leaks  into  the  tissues,  and  may  cause  thrombosis 
in  the  veins,  so  the  author  prefers  a  5  per  cent,  solution.  In 
several  instances  it  has  been  more  effective  than  large  doses  by 
mouth. 

SALICYLIC   ALLIES 

Acetyl-salicylic  acid,  or  aspirin,  C6Hi.O.COCH3.COOH,  of 
slightly  sour  taste  and  acid  reaction,  is  soluble  in  125  parts  of 
water  and  freely  in  alcohol.  It  gives  no  reaction  with  ferric 
chloride,  unless  previously  decomposed  by  alkalies  or  boiling 
with  water.  On  boiling  with  10  per  cent,  sodium  hydroxide 
solution  it  separates  into  its  components. 


SALICYLIC   ALLIES  485 

In  many  instances  it  has  proved  less  irritant  to  the  stomach 
than  either  salicylic  acid  or  sodium  salicylate,  but  not  infre- 
quently it  causes  hyperacidity  with  heartburn,  or  nausea  or 
vomiting.  The  claim  is  made  that  it  passes  through  the  stomach 
unchanged,  and  is  decomposed  in  the  alkaline  intestinal  contents 
to  form  sodium  salicylate  and  sodium  acetate;  but  sodium  car- 
bonate in  a  test-tube  does  not  so  decompose  it.  Theoretically, 
it  should  not  be  given  with  sodium  bicarbonate  or  other  alkali, 
lest  it  be  decomposed  in  the  stomach ;  but  in  the  author's  experi- 
ence the  bicarbonate  lessens  the  nausea  and  heartburn  which 
sometimes  result  from  its  use. 

Acetyl-salicylic  acid  has  greatly  replaced  quinine  in  the  affec- 
tions of  the  profession  and  the  laity,  and  is  prescribed  or  taken  in 
5 -grain  (0.3  gm.)  tablets  or  capsules  every  two  or  three  hours  for 
colds,  sore  throat,  neuralgia,  headache,  and  influenza.  It  is  also 
used  wherever  a  salicylate  is  indicated.  Williamson  (1902)  found 
that  it  reduced  the  sugar  in  the  urine  in  a  number  of  cases  of 
diabetes,  but  not  in  the  severe  cases,  but  Hall  found  that  60 
grains  (4  gm.)  a  day  for  twenty-seven  days  was  without  any  effect. 
It  is  strongly  diaphoretic. 

Toxicology. — There  are  a  number  of  reports  of  angioneurotic 
swelling  of  the  face  and  throat,  or  general  urticaria,  with  or  with- 
out nausea,  vomiting,  dizziness,  and  collapse.  These  are  due  to 
idiosyncrasy,  and  have  usually  followed  small  doses,  such  as  15 
grains  (i  gm.).  Von  Noorden  (1912)  says  that  in  three  of  his 
cases  acute  nephritis  followed  the  use  of  aspirin.  When  in  long 
contact  in  solution  quinine  and  acetyl-salicylic  acid  form  quino- 
toxin,  a  substance  possessing  some  of  the  actions  of  digitoxin. 
A  death  from  this  cause  is  reported. 

Novaspirin  is  the  methyl-citric-acid  ester  of  salicylic  acid; 
diplosal  is  the  salicylic-acid  ester  of  salicylic  acid;  and  diaspirin 
is  succinyl  disalicylic  acid.  It  is  claimed  for  all  these  that  they 
pass  through  the  stomach  unchanged. 

Salol,  or  phenyl  salicylate,  CgELj.OH.COOCeHs,  is  in  the  form 
of  crystals  with  a  characteristic  aromatic  odor.  It  gives  a  violet 
color  with  ferric  chloride.  It  is  soluble  in  alcohol,  but  is  insoluble 
in  water  and  practically  insoluble  in  gastric  juice.  In  a  test-tube 
alkalies  produce  the  odor  of  phenol,  and  in  the  alkaline  con- 
tents of  the  intestine  it  is  decomposed  and  goes  into  solution  as 
sodium  salicylate  and  phenol.  These  products  are  rapidly  ab- 
sorbed and  are  excreted  in  the  urine  as  salicyluric  acid  and 
phenol  sulphonates.  Whether  or  not  they  have  an  antiseptic 
effect  in  the  intestine  is  a  moot  question,  most  observers,  with  the 
exception  of  Herter,  perhaps,  having  failed  to  note  a  diminution 
of  the  indican,  or  any  other  indication  of  diminished  putrefaction. 


486  PHARMACOLOGY  AND  THERAPEUTICS 

Indeed,  phenol  itself,  judging  from  the  work  of  Richards  and 
Howland,  is  more  prone  to  increase  than  to  lessen  the  symptoms 
of  auto-intoxication.  Salol  is  sometimes  carried  through  the  in- 
testines without  change,  the  odor  being  recognized  in  the  feces. 

In  its  customary  dose  of  5  grains  every  three  or  four  hours 
salol  can  have  but  little  salicylic  effect,  and  it  is  really  a  phenol 
drug  rather  than  a  salicylate.  It  is  antipyretic  and  analgesic, 
however,  and  is  frequently  given  with  phenacetin  for  colds  or 
influenza.  In  chronic  colitis  it  is  given  in  capsules  with  a  few 
minims  of  castor  oil,  e.  g.,  5  grains  (0.3  gm.)  of  salol  and  5  min- 
ims (0.3  c.c.)  of  castor  oil.  In  diabetes,  Teschemacher  (1901) 
noted  a  decided  lessening  of  the  sugar  in  6  out  of  9  cases.  He 
gave  15  grains  (i  gm.)  four  times  a  day. 

As  shown  in  experimental  infections,  the  products  in  their 
excretion  tend  to  render  the  urine  antiseptic ;  hence  it  is  employed 
in  infections  of  the  urinary  tract. 

Salophen  is  salicylic-acetanilid.     Dose,  15  grains  (i  gm.). 

Saliphen  is  salicyl-para-phenetidin. 

Malakin  is  salicyliden-para-phenetidin. 

Mesotan  is  methyl-oxymethyl  ester  of  salicylic  acid,  with  the 
properties  of  a  volatile  oil.  It  is  more  irritant  than  methyl  salicyl- 
ate, so  is  used  diluted  with  an  equal  quantity  of  olive  oil. 

Spirosal  is  monoglycol  ester  of  salicylic  acid,  has  also  the  prop- 
erties of  a  volatile  oil,  and  is  used  in  alcoholic  or  oily  solution. 

Salicin  is  a  glucoside  obtained  from  willow  and  poplar  barks, 
It  is  bitter  and  is  not  nauseating.  In  either  the  stomach  or  the 
duodenum  it  splits  up  to  form  salicyl  alcohol  and  other  close 
relatives  of  salicylic  acid.  (See  Glucosides,  Part  I.)  Its  use 'is 
confined  to  the  milder  rheumatic  manifestations,  or  to  conditions 
of  the  stomach  which  prevent  ordinary  salicylic  medication. 
Dose,  20  grains  (1.3  gm.). 

Administration. — The  volatile  oil  types  of  salicylate  are  applied 
locally  over  the  inflamed  parts  either  by  rubbing  or  on  a  compress. 
Internally  they  are  given  in  capsules.  Aspirin,  salicin,  salol,  etc., 
are  best  given  in  capsules,  but  may  be  employed  in  tablet  form. 

COLCHICUM 

Though  it  bears  no  relation  to  salicylic  acid,  colchicum, 
because  of  its  use  in  gout,  may  properly  be  mentioned  here.  Both 
the  seed  and  the  corm  of  Colchicum  aulumnale  (fam.  Liliacecc], 
a  crocus-like  plant,  are  official,  the  seed  being  required  by  the 
United  States  Pharmucopceiu  to  contain  not  less  than  0.45  per 
cent,  of  the  alkaloid  colchicine,  and  the  corm  not  less  than  0.35 
per  cent. 


PHENYL-CINCHONINIC   ACID  487 

Preparations  and  Doses. — 

(a)  Colchicum  seed,  dose,  3  grains  (0.2  gm.). 
Fluidextract,  dose,  3  minims  (0.2  c.c.). 
Tincture,  10  per  cent.,  dose,  30  minims  (2  c.c.). 

(b)  Colchicum  corm,  dose,  4  grains  (0.25  gm.). 

Extract  (1.25  to  1.55  per  cent,  of  colchicine),  dose,  i 
grain  (0.06  gm.). 

(c)  Colchicine,  dose  T^  grain  (0.0005  g111-)- 

The  Wine  of  Colchicum  Root,  N.  F.,  40  per  cent.,  and 
the  Wine  of  Colchicum  Seed,  N.  F.,  10  per  cent., 
are  also  employed. 

Pharmacology. — Colchicum  is  a  gastro-intestinal  irritant,  the 
larger  therapeutic  doses  sometimes  causing  nausea,  vomiting,  and 
diarrhea.  In  poisoning  there  is  intense  gastro-intestinal  irrita- 
tion, with  vomiting,  pain,  and  bloody  stools;  and  there  are  irrita- 
tion of  the  kidneys  (a  remote  local  effect),  collapse,  and,  some- 
times, an  ascending  paralysis,  beginning  in  the  legs.  Death  takes 
place  from  paralysis  of  respiration.  It  has  resulted  from  J¥  grain 
(0.003  g111-)  °f  colchicine  in  a  case  of  gout  with  nephritis.  Diar- 
rhea calls  for  stoppage  of  the  drug. 

There  are  no  constant  effects  upon  the  uric-acid  excretion  in 
gout  or  in  health,  and  there  is  nothing  in  the  pharmacology  of 
colchicum  that  explains  its  use  in  gout.  Yet  it  seems  to  have 
great  power  in  the  acute  attack  to  relieve  the  pain  and  swelling 
of  the  joints  and  to  shorten  the  attack.  In  the  words  of  von 
Noorden,  "Colchicum  accelerates  the  critical  outpouring  of  uric 
acid  that  accompanies  gouty  seizures,  but  is  inert  in  the  intervals 
between  the  attacks,  and  in  chronic  and  atypical  gout."  But 
Fine  and  Chace,  Hanzlik,  and  others  find  that  any  value  that  the 
drug  may  have  in  gout  is  entirely  unrelated  to  uric  acid  excretion. 

PHENYL-CINCHONINIC   ACID 

Phenyl-cinchoninic  acid,  phenyl-quinoline-carboxylic  acid, 
marketed  under  the  proprietary  name  atophan,  is  official;  dose,  8 
grains  (0.5  gm.).  It  is  insoluble  in  water  and  alcohol  and  has  a 
biting  bitter  taste.  There  is  abundant  evidence  that  this  sub- 
stance in  both  normal  and  gouty  subjects  acts  on  the  kidneys 
to  increase  the  amount  of  urine  and  the  excretion  of  all  the  ele- 
ments of  the  urine,  but  especially  the  uric  acid.  Fine  and  Chace 
found  that  it  brought  the  uric  acid  of  the  blood  to  a  percentage 
away  below  normal.  McLester,  after  the  large  dose  of  45  grains 
(3  gm.),  noted  that  in  three  hours  the  uric  acid  of  the  blood  was 
halved  and  the  amount  of  urine  trebled,  in  the  next  three  hours 
the  blood  uric  acid  was  again  halved,  but  the  total  urine  was  small, 


488  PHARMACOLOGY   AND   THERAPEUTICS 

and  in  the  next  three  hours  there  was  no  change  in  the  blood  uric 
acid,  both  the  uric  acid  in  the  blood  and  the  excretion  of  urine 
having  dropped  to  a  low  point.  He  concludes  that  atophan 
stimulates  the  kidneys  to  a  marked  degree,  and  that  the  excessive 
activity  is  followed  by  a  period  of  fatigue  and  comparative  in- 
activity. Brugsch,  Folin  and  Denis,  and  others  believe  that  the 
drug  does  not  mobilize  deposited  urates,  while  Smith  and  Hawk 
consider  that  a  rather  high  and  long-continued  excretion  in  cases 
of  gout  must  be  explained  by  urate  mobilization.  Daniels  found 
that  lithium  citrate  alone  had  no  influence  on  the  excretion  of 
urine,  but  that  when  it  was  given  in  doses  of  20  to  30  grains  (1.3-2 
gm.)  a  day  to  a  person  already  getting  atophan  the  uric  acid 
elimination  was  increased  55  per  cent.  She  figured  that  the 
lithium  salt  induced  mobilization  and  brought  the  uric  acid  into 
the  blood  to  be  excreted.  In  any  case  it  is  recommended  that 
alkalies  and  plenty  of  water  be  administered  during  the  atophan 
treatment.  Occasional  untoward  effects  are  gastric  irritation, 
abdominal  pain,  diarrhea,  purpura,  urticaria,  a  scarlatiniform 
rash,  and  collapse. 

Cimicifuga,  black  snakeroot,  is  a  bitter  rhizome  of  the  north- 
eastern United  States,  sometimes  employed  in  gout  and  rheuma- 
tism. The  dose  of  the  fluidextract  is  15  minims  (i  c.c.);  of  the 
extract,  4  grains  (0.25  gm.). 

Piperazine,  diethylene-diamine,  is  hygroscopic  and  very  sol- 
uble in  water.  It  is  alkaline,  forms  salts  with  acids,  and  is 
incompatible  writh  alkaloidal  salts,  metallic  salts,  tannic  acid, 
acetanilid,  and  acet-phenetidin.  On  the  finding  that  its  salt  with 
uric  acid  was  readily  soluble,  this  drug  was  brought  forward  as  a 
remedy  in  gout  and  the  uric-acid  diathesis;  but  its  value  is  ques- 
tionable, for  in  the  urine  it  is  usually  found  in  combination  with 
the  mineral  acids  rather  than  with  uric  acid.  Starling  reports  it, 
however,  as  promoting  the  excretion  of  uric  acid  by  the  tubule 
cells,  as  shown  in  kidney  experiments.  Hanzlik  states  that 
equally  worthless  are  piperazine,  lycetol,  lysidin,  piperidine, 
quinic  acid,  quinidine,  sidonal,  urol,  and  urosin. 

DISINFECTANTS   AND   ANTISEPTICS 

A  disinfectant  is  an  agent  that  has  the  power  to  destroy 
microbic  life,  i.  e.,  it  is  a  germicide.  An  antiseptic  is  an  agent  that 
tends  to  retard  the  growth  of  microorganisms. 

A  deodorant  or  deodorizer  is  an  agent  that  will  destroy  or  over- 
come a  foul  odor.  It  may  or  may  not  be  disinfectant.  Examples 
of  such  are:  (i)  For  general  use,  chlorinated  lime,  cologne  water, 
charcoal,  the  smoke  of  burning  paper,  burning  straw,  or  burn- 


DISINFECTANTS  AND   ANTISEPTICS  489 

ing  coffee;  (2)  for  bad  breath,  antiseptic  solution,  N.  F.  (contain- 
ing boric  acid,  thymol,  eucalyptol,  methyl  salicylate,  oil  of 
thyme,  sodium  salicylate,  sodium  benzoate,  alcohol,  and  water), 
or  hydrogen  dioxide;  (3)  for  fetid  breath,  creosote;  (4)  in  foul 
ulcers,  potassium  permanganate,  hydrogen  dioxide,  or  formal- 
dehyd. 

A  preservative  is  an  antiseptic  agent  used  to  prevent  microbic 
changes  (fermentation,  putrefaction)  in  organic  material,  such  as 
food,  medicines,  etc.  Preservatives  are  so  extensively  employed 
in  butter,  milk,  soups,  vegetables,  meat,  etc.,  that  it  is  possible 
to  ingest  a  large  quantity  of  one  preservative  or  small  doses  of 
each  of  several  preservatives  at  a  single  meal.  Many  of  them 
retard  decomposition  without  checking  the  activity  of  pathogenic 
germs. 

Sterilization  is  any  process  by  which  a  substance  is  made  germ- 
free.  It  usually  implies  destruction  of  germs  by  heat  at  100°  C. 
(212°  F.)  or  higher.  Pasteurization  is  a  form  of  partial  steriliza- 
tion at  1 60°  F.  for  half  an  hour.  It  is  used  for  milk. 

The  ideal  antiseptic  or  disinfectant  for  use  about  the  body  is 
one  with  a  maximum  action  on  microorganisms  and  a  minimum 
action  on  the  body  tissues.  Of  blood  disinfectants,  quinine  in 
malaria  and  salvarsan  in  syphilis  would  seem  most  nearly  to 
approach  this  ideal;  though  their  destructive  effect  is  limited  to 
certain  organisms  only. 

The  germicidal  value  of  many  disinfectants  is  seriously  inter- 
fered with  by  organic  matter,  especially  blood-serum,  so  that  the 
germicide  that  is  strongest  in  the  test-tube  may  be  the  weakest 
when  in  contact  with  the  body  tissues.  Moreover,  many  ger- 
micides are  decidedly  more  destructive  to  human  tissues  than  to 
germs,  so  that  their  use  may  result  in  a  lowering  of  the  local  resist- 
ance of  the  patient.  (See  Lambert's  report  on  Iodine,  page  499.) 

Tests  with  Albuminous  Fluids. — On  mixing  hydrocele  fluid 
with  an  equal  quantity  of  an  antiseptic  solution  of  sodium  aurate, 
argyrol,  and  protargol  (Verhoeff,  1906),  and  of  collargol,  albargin, 
ichthargan,  argentamine,  largin,  and  argonin  (Derby,  1909),  the 
germicidal  effects  were  inhibited.  With  the  same  method, 
Verhoeff  and  Ellis  (1907)  found  that  lysol,  i  per  cent.,  creolin, 
i  per  cent.,  listerine,  100  per  cent.,  and  liquor  antisepticus, 
X.  F.,  100  per  cent.,  failed  to  kill  Staphylococcus  aureus  in  two 
hours.  The  last-named  authors  also  demonstrated  that  neither 
acetozone  i  :  1000,  alphozone  i  :  1000,  nor  zinc  sulphocarbolate, 
i  per  cent.,  mixed  with  solution  of  albumin,  was  successful  in 
sterilizing  typhoid  culture  in  twenty-four  hours;  and  that,  mixed 
with  albumin,  alkalol,  100  per  cent.,  borol,  50  per  cent.,  alkathy- 
mol,  ico  per  cent.,  glycothymoline,  100  per  cent.,  zinc  sulpho- 


490 


PHARMACOLOGY   AND   THERAPEUTICS 


carbolate,  i  per  cent.,  and  cuprol,  5  per  cent.,  each  failed  to  de- 
stroy Staphylococcus  aureus  in  four  hours.  (See  also  under 
Silver.) 

Post  and  Nicoll  (1910)  made  extensive  tests,  and  reported  the 
number  of  colonies  in  a  loopful  of  test  solution  after  different 
lengths  of  time. 

From  their  work  the  following  table  is  compiled : 


SOLUTION" 

STREPTO- 
COCCUS 

GONO- 
coccus 

PNEUMO- 
coccus 

BACILLUS 
TYPHOSUS 

AFTER 
WHAT  TIME 
IN  MINUTES 

I.  Silver  preparations: 
Argyrol.  50  per  cent  

Oo 

3,000 

00 

o 

One 

0 

2,000 

20O 

o 

Thirty. 

Argyrol,  10  per  cent  

OO 

2,000 

OO 

o 

One 

II 

0 

7 

0 

Thirty. 

Protargol,  10  per  cent  

600 

2OO 

<--        ° 

^  i  ,000 

One. 

o 

o 

0 

o 

Thirty. 

Silver  nitrate,  i  per  cent.  .  .  . 

o 

o 

0 

o 

One. 

Silver  nitrate,  i  :  1000  

o 

o 

<-° 

^20 

t;oo 

One 

o 

o 

o 

0 

Thirty. 

Silver  nitrate,  i  :  5000  

^  I 

o 

5° 

00 

One. 

<II 

0 

o 

0 

1,000 
o 

o 

Thirty. 

II.  Mercury  preparations: 
Mercuric  bichloride,  i  :  500 

2,000 
o 

3,000 

I 

3,000 
o 

0 

o 

One. 

Thirty. 

Mercuric  biniodide,  i  :  1000 

III.  Phenols: 
Phenol,  5  per  cent  

IO 

o 
o 

0 

o 
o 

OO 

4,000 

0 

o 

0 

o 

One. 

Thirty. 

One. 

Phenol    i  per  cent  

00 

4,000 

8,000 

6,000 

One. 

Trikresol,  i  per  cent  

500^ 

o 

0 

o 

4,000 
o 

1,000 
o 

Thirty. 
One. 

Trikresol,  0.3  per  cent  

4,000 

2,000 

10,000 

2,000 

One. 

Lysol    i  5  per  cent  

0 

0 

400 

10,000 

One. 

0 

0 

0 

o 

Thirty. 

Lysol   i  '  1000       

00 

500 

6,000 

00 

One. 

12 

1,000 

4,000 

00 

Thirty. 

Creolin   i  per  cent  

0 

25 

300 

J 

One. 

o 

o 

o 

o 

Thirty. 

IV.  Iodine  preparations: 
Tincture  (7  per  cent.)  

o 

0 

0 

o 

One. 

Iodine        i    1 

Potassium  iodide  .  .      I 
Water.  .  .  .to  make  100    J 

0 

0 

o 

0 

One. 

V.  Formaldehyde  preparations: 
Liquor  formaldehydi,  U.S.  P. 

0 

o 

0 

o 

One. 

Liquor  formaldehydi,    i   per 

10,000 

4,000 

5,000 

OO 

One. 

500 

1,000 

JOO 

50 

Thirty. 

DISINFECTANTS   AND   ANTISEPTICS 


4QI 


SOLUTION 

STREPTO- 
COCCUS 

GONO- 

COCCDS 

PNEUMO- 
coccus 

BACILLUS 
TYPHOSUS 

AnER 
WHAT  TIME 

IN  MINUTES 

VI.  Akohol: 
20  per  cent.       

300 

300 

8,000 

4,000 

One. 

3 

o 

8,000 

2,000 

Thirty. 

30  per  cent  

25 

o 

2,000 

300 

One. 

50  per  cent  

0 

o 

o 

o 

One. 

70  per  cent  

o 

o 

o 

o 

One. 

VII.  Miscellaneous: 
Tincture  of  green  soap  

o 

0 

o 

o 

One. 

Hydrogen  dioxide  

2OO 

1  ,000 

2  OOO 

o 

One 

O 

o 

0 

o 

Thirty. 

Thiersch's  solution        

O 

o 

?  OOO 

^-10,000 

One. 

O 

o 

o 

0 

o 

Thirty. 

Potassium      permanganate, 
i  :  1000  

CO 

^,000 

Oo 

2,000 

One 

o 

o 

2,000 

o 

Thirty. 

Copper  sulphate,  i  per  cent. 

00 

5,000 

4,000 
2,000 

6,000 

4,000 

3,000 

I,  OOO 

One. 

Thirty. 

Boric  acid,  saturated  (  i  :  18) 

CO 

2,000 

3,000 
2,000 

10,000 
5,000 

CO 

00 

One. 

Thirty. 

Potassium     chlorate,    satu- 
rated, 6.6  per  cent  

00 

3,000 

IO  OOO 

CO 

One. 

5,000 

2,000 

5,000 

00 

Thirty. 

Glycerin  

2,000 

6.000 

OO 

Oo 

One. 

1,000 

4,000 

00 

00 

Thirty. 

Distilled  water  

10,000 

4,000 

10,000 

oo 

One. 

These  results  establish:  (i)  The  reliability  and  prompt 
action  of  a  few  simple  germicides,  such  as  tincture  of  green  soap, 
alcohol  in  solutions  above  50  per  cent.,  silver  nitrate  as  dilute  as 
i  :  1000,  the  iodine  solutions,  and  5  per  cent,  phenol.  (2)  The 
unreliability  of  many  agents  prevalently  supposed  to  be  effective 
germicides.  (3)  The  slow  action  of  mercuric  chloride,  though 
when  given  hours  to  act  it  is  effective  in  high  dilutions. 

Classification,  according  to  the  nature  of  the  agent: 

1.  Heat  and  cold. 

2.  Oxidizers. 

3.  Deoxidizers. 

4.  Free  halogens  and  their  compounds. 

5.  Metals  and  metallic  salts. 

6.  Miscellaneous  inorganic  compounds. 

7.  Phenol  and  its  allies. 

8.  Miscellaneous  organic  compounds. 


492  PHARMACOLOGY    AND   THERAPEUTICS 

I.  HEAT   AND    COLD 

The  surest  disinfection  of  all  for  soiled  dressings  is  burning. 
In  the  preparation  of  sterile  dressings  there  is  nothing  more 
destructive  to  bacteria  or  more  penetrant  to  fabrics  than  super- 
heated steam — i.  e.,  steam  under  5  to  15  pounds  pressure,  which 
gives  it  a  temperature  of  220°  to  230°  F.  Doty,  at  the  New  York 
Quarantine  Laboratory,  found  that  a  moist  heat  of  230°  F. 
killed  all  germs  in  fifteen  minutes,  even  anthrax  spores,  and  even 
when  placed  in  the  center  of  large  and  tightly  rolled  bundles.  Next 
in  value  is  boiling  in  water  (212°  F.),  as  of  instruments.  Liquids 
may  themselves  be  boiled,  unless  some  constituent  of  the  liquid 
is  destroyed  or  volatilized  by  heat.  These  methods  are  spoken  of 
as  methods  of  sterilization.  Pasteurization  is  incomplete  ster- 
ilization, the  liquid  being  exposed  to  a  temperature  of  about  160° 
F.  for  half  an  hour;  this  destroys  99  per  cent,  of  the  bacteria  of 
milk.  Dry  heat  is  less  effective  than  moist,  and  some  of  the 
bacteria  which  succumb  quickly  to  boiling  will  resist  for  a  time  a 
dry  heat  of  350°  or  400°  F. 

Cold  is  preservative,  but  not  sterilizing,  as  in  refrigerators  and 
cold  storage;  but  it  is  not  very  active  in  destroying  bacteria,  and 
more  or  less  bacterial  action  can  go  on  in  spite  of  a  temperature 
below  that  of  freezing.  In  ice-cream,  for  example,  kept  at  a  tem- 
perature of  — 5.8°  F.  ( — 21°  C.),  the  government  experts  found 
that  in  most  cases  the  number  of  living  bacteria  diminished  in  the 
cold  for  several  days,  then  showed  a  pronounced  rise  in  numbers, 
as  if  the  bacteria  had  become  inured  to  the  cold.  As  demonstrat- 
ing the  failure  of  cold  to  check  microbic  growth,  one  sample  of 
ice-cream,  when  fresh,  showed  811,000  bacteria  per  gram;  after 
eighteen  hours,  1,010,509;  after  forty-two  hours,  3,349,733;  and 
after  sixty-six  hours,  4,405,000.  This  was  while  it  was  kept 
packed  in  a  freezing  mixture  of  ice  and  salt.  Mitchell  found 
that  the  typhoid  bacillus  survived  in  ice-cream  for  from  twelve 
to  thirty-nine  days. 

Successful  cold  storage  requires  the  greatest  care  in  the  regu- 
lation of  both  temperature  and  moisture;  for  example,  fresh  eggs 
will  stand  a  temperature  of  28°  F.,  but  when  three  months  old 
will  freeze  at  a  temperature  below  30°  F. 

II.  OXIDIZERS 

These  act  by  liberating  oxygen,  and  in  their  action  are  them- 
selves quickly  destroyed.  They  are  very  inferior  disinfectants, 
but  are  effective  deodorizers.  They  readily  and  permanently 
destroy  many  colors,  and  are  used  as  bleaching-agents. 

i.  Liquor  hydrogenii  dioxidi,  peroxide  of  hydrogen,  H2O2,  is 


DEOXIDIZERS  493 

a  watery  liquid,  rather  unstable,  and  capable  of  yielding  10 
volumes  of  free  oxygen.  The  Pharmacopoeia  states  that  it  keeps 
better  if  a  pledget  of  cotton  is  used  to  stopper  the  bottle  instead 
of  a  cork.  It  destroys  cork,  rubber  tissue,  catgut,  etc.,  and  in 
contact  with  pus,  blood,  and  other  organic  liquids  splits  into  water 
and  oxygen,  giving  off  the  oxygen  so  actively  that  it  effervesces 
and  produces  a  foam.  In  a  cavity  without  free  exit  this  gas  may 
burrow  into  the  tissues,  with  extension  of  the  infection.  It  is  a 
powerful  deodorizer,  and  in  dilution  with  not  more  than  one  or 
two  volumes  of  water,  is  a  valuable  germicide.  In  the  experi- 
ments of  the  Hygienic  Laboratory  (1912)  cultures  of  typhoid 
bacilli  were  found  sterile  after  an  exposure  of  two  and  one-half 
minutes  to  50  per  cent,  solution.  (See  also  table  of  Post  and 
Nicoll.)  It  is  much  employed  as  a  gargle  or  mouth-wash,  as  in 
tonsillitis,  diphtheria  or  pyorrhoea  alveolaris,  or  for  deeply  furred 
tongue,  and  as  a  surgical  cleanser  in  pus  conditions.  The  author 
has  employed  it  in  the  colon  in  intestinal  putrefaction,  to  check 
the  growth  of  anaerobic  bacteria  by  liberating  oxygen;  but  it 
proved  too  irritating  to  the  bowel.  It  is  also  irritant  in  the  throat. 

2.  Potassium  permanganate,  KMn04,  in  aqueous  solution, 
at  once  decomposes  when  it  comes  in  contact  with  organic  matter, 
giving  up  oxygen  without  effervescence  and  being  reduced  to  the 
brown,  insoluble  potassium  manganate.     It  is  a  chemic  antidote 
to  certain  oxidizable  poisons,  such  as  morphine,  phenol,  and 
hydrocyanic  acid,  is  a  local  irritant  and  stimulant,  as  in  persistent 
sinuses,  and  in  i  :  10,000  to  i  :  1000  solution,  is  an  antiseptic  and 
deodorizer,  as  of  foul  ulcers  and  foul  cancers.    The  crystals  or  the 
concentrated  solution  have  been  used  with  success  locally  in 
snake-bite.     Von  Adelung  (1913)  advises  a  2  per  cent,  solution  in 
ivy-poisoning.     Death  in  a  woman  is  reported  from  the  corrosive 
effects  of  2\  drams  (10  gm.)  of  the  crystals  swallowed  with  suicidal 
intent. 

3.  Sodium  perborate,  containing  about  9  per  cent,  of  available 
oxygen,  is  a  white  powder  soluble  in  cold  water.     It  is  stable  in 
cool  and  dry  air,  but  in  warm  or  moist  air  gives  off  its  oxygen. 

III.  DEOXIDIZERS 

These  are  the  sulphite  group,  viz.,  sulphur  dioxide  and  sul- 
phurous acid,  sodium  sulphite,  sodium  bisulphite,  and  sodium 
thiosulphate  (hyposulphite).  The  sulphites  absorb  oxygen  to 
form  sulphates.  They  will  destroy  many  colors,  but  these  on 
exposure  to  the  air  tend  to  be  restored  through  reoxidation.  Fer- 
rous sulphate  is  of  this  group,  as  it  takes  up  oxygen;  its  chief  use 
is  in  water-closets,  sinks,  and  cess-pools. 


494  PHARMACOLOGY   AND   THERAPEUTICS 

Sulphur  dioxide  (SO2),  formed  by  burning  sulphur,  is  used 
for  the  disinfection  of  rooms.  It  bleaches  fabrics,  though  these 
may  slowly  regain  their  color  on  exposure  to  the  air.  As  a  disin- 
fectant it  is  not  very  efficient,  but  the  New  York  Department  of 
Health  allows  room  disinfection  with  eight  hours'  exposure  to  the 
fumes  of  4  pounds  of  sulphur  for  each  1000  cubic  feet  of  air-space. 
It  has  the  greatest  disinfectant  power  when  used  with  steam  or 
moist  air,  but  then  is  more  destructive  to  fabrics  and  colors.  The 
dry  sulphur  dioxide  is  effective  in  destroying  vermin,  but  it  does 
not  readily  penetrate  cracks. 

IV.  FREE   HALOGENS  AND   THEIR   COMPOUNDS 

Chlorine  and  the  Hypochlorites. — Chlorine  gas  is  set  free 
from  chlorinated  lime  on  contact  with  moisture,  or  it  may  be 
prepared  by  adding  dilute  sulphuric  acid  to  a  mixture  of  equal 
parts  of  manganese  dioxide  and  sodium  chloride.  Chlorine  water, 
0.4  per  cent.,  and  the  solution  of  sodium  hypochlorite  (Labarraque's 
solution),  are  employed  as  gargles,  and  a  solution  of  potassium 
hypochlorite  (eau  de  Javelle)  is  used  to  bleach  linen.  These 
liquids  are  caustic  and  are  not  suitable  for  application  to 
wounds.  Ant  if  or  min  is  an  alkaline  hypochlorite  used  to  dis- 
solve tissue,  blood,  pus,  and  mucus  in  the  examination  of  sputum 
for  tubercle  bacilli. 

A  favorite  procedure  for  the  disinfection  of  the  surgeon's 
hands  is  to  moisten  them  and  then  rub  them  together  with  a  little 
chlorinated  lime  and  washing-soda;  the  soluble  sodium  hypochlo- 
rite and  free  chlorine  are  generated,  and  serve  as  effective  skin 
germicides.  Chlorine  is  a  very  irritant  gas,  and  is  a  powerful  per- 
manent bleaching-agent,  destroying  wall-paper,  fabrics,  etc. 

Theory  of  Action. — In  an  investigation  of  the  action  of  chlo- 
rine compounds,  Dakin  finds  no  support  for  the  theory  that  their 
antiseptic  action  is  due  to  the  liberation  of  oxygen  in  the  pres- 
ence of  organic  matter,  but  has  ascertained  that  free  chlorine  con- 
verts some  of  the  >NH  groups  of  the  proteins  into  >NC1  groups, 
producing  new  substances  which  are  known  as  chloramins  and 
are  antiseptic. 

Chlorinated  lime,  CaClo.Ca(OCl)2,  is  commonly  known  as 
"chloride  of  lime."  It  has  been  much  employed  in  privies, 
sinks,  cess-pools,  etc.,  and  for  the  purification  of  drinking-water. 
For  the  latter  purpose  a  level  teaspoonful  of  the  powder  is  dis- 
solved in  a  pint  of  water,  and  of  this  one  teaspoonful  is  mixed 
with  two  gallons  of  the  water  to  be  purified,  i.  e.,  i  part  in 
2.000.000.  In  this  dilution  it  gives  no  taste.  Chlorinated  lime 
deteriorates  rapidly  on  exposure  to  air. 


FREE   HALOGENS   AND    THEIR    COMPOUNDS  495 

Dakin  and  Dunham  have  found  para-sulphon-di-chloramino- 
benzoic  aoid  to  be  the  most  suitable  agent  for  the  disinfection  of 
drinking-water,  a  solution  of  i  :  300,000  being  able  to  sterilize 
a  heavily  contaminated  water  in  about  thirty  minutes,  and  giving 
a  barely  perceptible  taste.  It  keeps  well  if  in  tablet  form. 

The  Dakin-Carrel  Treatment  has  become  famous  as  a  method 
for  the  continuous  disinfection  of  wounds,  the  antiseptic  employed 
being  a  solution  of  sodium  hypochlorite  (NaOCl)  as  obtained  in 
Daufresne's  modification  of  Dakin's  solution.  The  formula  of 
this  solution  as  given  by  Carrel  (Jour.  Amer.  Med.  Assoc., 
December  9,  1916)  is  as  follows: 

Preparation  of  Dakin's  Solution. — Daufresne's  Technic. — 
Dakin's  solution  is  a  solution  of  sodium  hypochlorite  for  surgical 
use,  the  characteristics  of  which,  established  after  numerous  tests 
and  a  long  practical  experience,  are  as  follows: 

(a)  Complete  Absence  of  Caustic  Alkali. — The  absolute  neces- 
sity for  employing  in  the  treatment  of  wounds  a  solution  free  from 
alkali  hydroxide  excludes  the  commercial  Javelle  water,  Labar- 
raque's  solution,  and  all  the  solutions  prepared  by  any  other 
procedure  than  the  following : 

(b)  Concentration. — The  concentration  of  sodium  hypochlorite 
must  be  exactly  between  0.45  and  0.50  per  cent.     Below  0.45 
per  cent,  of  hypochlorite  the  solution  is  not  sufficiently  active; 
above  0.50  per  cent,  it  becomes  irritating. 

Chemicals  Required  for  the  Preparation. — Three  chemical 
substances  are  indispensable  to  Dakin's  solution:  chlorinated 
lime,  anhydrous  sodium  carbonate,  and  sodium  bicarbonate. 
Among  these  three  products  the  latter  two  are  of  a  practically 
adequate  constancy,  but  this  is  not  the  case  with  the  first. 
Its  content  in  active  chlorine  (decoloring  chlorine)  varies  within 
wide  limits,  and  it  is  absolutely  indispensable  to  titrate  it  before 
using  it. 

Titration  of  the  Chlorinated  Lime. — There  must  be  on  hand  for 
this  special  purpose: 

A  25  c.c.  buret  graduated  in  o.i  c.c. 

A  pipet  gaged  for  10  c.c. 

A  decinormal  solution  of  sodium  thiosulphate  (hyposulphite). 

The  material  for  the  dosage  thus  provided,  a  sample  of  the 
provision  of  chlorinated  lime  on  hand,  is  taken  up  either  with  a 
special  sound  or  in  small  quantities  from  the  mass  which  then 
are  carefully  mixed. 

Weigh  out  20  gm.  of  this  average  sample,  mix  it  as  completely 
as  possible  with  i  liter  of  ordinary  water,  and  leave  it  in  contact 
for  a  few  hours,  agitating  it  from  time  to  time.  Filter. 

Measure  exactly  with  the  gaged  pipet  10  c.c.  of  the  clear 


496  PHARMACOLOGY   AND   THERAPEUTICS 

fluid;  add  to  it  20  c.c.  of  a  i  :  10  solution  of  potassium  iodid  and 
2  c.c.  of  acetic  or  hydrochloric  acid.  Drop,  a  drop  at  a.time,  into 
this  mixture  a  decinormal  solution  of  sodium  thiosulphate  until 
decoloration  is  complete. 

The  number  of  cubic  centimeters  of  the  hypochlorite  solution 
required  for  complete  decoloration,  multiplied  by  1.775,  gives  the 
weight  of  the  active  chlorine  contained  in  100  gm.  of  the  chlorin- 
ated lime. 

This  figure  being  known,  it  is  applied  to  the  accompanying 
table,  which  will  give  the  quantities  of  chlorinated  lime,  of  sodium 
carbonate,  and  of  sodium  bicarbonate  which  are  to  be  employed 
to  prepare  10  liters  of  Dakin's  solution: 

Titer  of  chlorin-  Chlorinated  Anhydrous  sodium      Sodium  bicarbonate, 

ated  lime.  lime,  gm.  carbonate,  gm.  gm. 

20  230  115  96 

21  220  no  92 

22  210  105  88 

23  20O  IOO  84 

24  IQ2  96  80 

25  184  92  76 

26  177  89  72 

27  170  85  70 

28  164  82  68 

29  159  80  66 
3°  154  77  64 

31  148  74  62 

32  .    144  72  60 

33  HO  70  59 

34  135  68  57 

35  132  66  55 

36  128  64  53 

37  124  62  52 

Example:  If  it  required  16.6  c.c.  of  the  decinormal  solution  of 
the  sodium  thiosulphate  for  complete  decoloration,  the  titer  of  the 
chlorinated  lime  in  active  chlorine  is:  16.6  X  i-775  =  29.7  per 
cent.  The  quantities  to  be  employed  to  prepare  10  liters  of  the 
solution  will  be  in  this  case: 

Chlorinated  lime 154  ^m. 

Dry  sodium  carbonate 77  gm. 

Sodium  bicarbonate 62  gm. 

Of  crystalline  sodium  carbonate  220  gm.  may  be  used  instead 
of  the  80  gm.  of  dry  carbonate. 

Preparation  of  Dakin's  Solution. — To  prepare  TO  liters  of  the 
solution: 

1.  Weigh  exactly  the  quantities  of  chlorinated  lime,  sodium 
carbonate,  and  sodium  bicarbonate  which  have  been  determined 
in  the  course  of  the  preceding  trial. 

2.  Place  in  a  1 2-liter  jar  the  chlorinated  lime  and  5  liters  of 


FREE    HALOGENS   AND    THEIR    COMPOUNDS  497 

ordinary  water,  agitate  vigorously  for  a  few  minutes,  and  leave  in 
contact  for  from  six  to  twelve  hours,  over  night,  for  instance. 

3.  At  the  same  time  dissolve,  cold,  in  the  five  other  liters  of 
water  the  sodium  carbonate  and  the  bicarbonate. 

4.  Pour  all  at  once  the  solution  of  the  sodium  salts  into  the  jar 
containing  the  maceration  of  chlorinated  lime,  agitate  vigorously 
for  a  few  moments,  and  leave  it  quiet  to  permit  the  calcium 
carbonate  to  settle  as  it  forms.     At  the  end  of  half  an  hour,  siphon 
the  liquid  and  filter  it  through  double  paper  to  obtain  an  entirely 
limpid  product,  which  must  be  protected  from  light. 

Titration  of  Dakin's  Solution. — It  is  wise  precaution  to  verify, 
from  time  to  time,  the  titer  of  the  solution.  This  titration  utilizes 
the  same  material  and  the  same  chemical  substances  as  are  used  to 
determine  the  active  chlorine  in  the  chlorinated  lime: 

Measure  out  10  c.c.  of  the  solution,  add  20  c.c.  of  i  :  10  solu- 
tion of  potassium  iodid,  and  2  c.c.  of  acetic  or  hydrochloric  acid. 
Drop,  a  drop  at  a  time,  into  this  mixture  a  decinormal  solution 
of  sodium  thiosulphate  until  decoloration  is  complete.  The 
number  of  cubic  centimeters  employed  multiplied  by  0.03725  will 
give  the  weight  of  the  sodium  hypochlorite  contained  in  100  c.c.  of 
the  solution.  A  solution  is  correct  when,  under  the  conditions 
given  above,  from  12  to  13  c.c.  of  decinormal  thiosulphate  are 
required  to  complete  the  decoloration:  13  X  0.03725  =  0.485  per 
cent,  of  NaOCl. 

The  Test  for  the  Alkalinity  of  Dakin's  Solution. — Pour  into  a 
glass  about  20  c.c.  of  the  fluid,  and  drop  on  the  surface  a  few 
centigrams  of  phenolphthalein  in  powdered  form.  Dakin's  solu- 
tion, correctly  prepared,  gives  absolutely  no  change  in  tint. 

It  is  to  be  noted  that  the  solution  must  be  of  reasonable 
freshness,  exactly  neutral,  and  absolutely  of  a  concentration 
between  0.45  and  0.50  per  cent.  The  tubes  must  be  so  placed 
that  the  liquid  runs  down  and  not  up  into  the  wound,  and  must 
be  so  arranged  as  to  bring  and  keep  the  liquid  in  contact  with 
every  part  of  the  wound  surface.  To  insure  continuous  contact 
and  to  hold  the  tubes  in  place  fluff  gauze  is  stuffed  between  the 
tubes.  The  antiseptic  is  rapidly  taken  up  by  the  tissues,  so  its 
renewal  is  secured  by  an  instillation  of  the  liquid  every  two  hours. 
At  no  time  is  enough  solution  allowed  to  run  in  to  more  than  fill 
the  wound  and  saturate  the  packing.  The  method  is  neither  one 
of  drainage  nor  of  irrigation,  nor  a  continuous  drip  process,  for 
no  liquid  flows  except  during  the  two-hourly  instillations.  The 
skin  for  3  or  4  inches  on  all  sides  is  protected  by  a  covering  of 
bandage  gauze  impregnated  with  sterile  petrolatum  or  vaseline. 
As  the  solution  can  dissolve  dead  tissue,  clots,  etc.,  all  vessels 
must  be  tied  off,  otherwise  there  may  be  secondary  hemorrhage. 


498  PHARMACOLOGY   AND   THERAPEUTICS 

Pain  is  an  indication  that  the  solution  is  not  right,  or  if  during  the 
instillation,  that  the  liquid  is  being  allowed  to  run  in  under  too 
much  pressure. 

This  liquid  not  only  forms  chloramins  as  described  above  of  a 
disinfectant  value  14  to  22  times  that  of  phenol,  but,  in  addition, 
through  its  hypertonicity  induces  a  flow  of  lymph  from  the  wound 
surfaces  and  so  prevents  any  absorption  of  toxic  products  through 
the  lymph-channels.  In  the  Dakin-Carrel  treatment  the  absence 
of  lymphatic  involvement  is  striking. 

Dichloramin-T. — This  is  toluene  parasulphondichloramin,  an 
antiseptic  prepared  by  Dakin  to  do  away  with  the  difficulties  of 
the  technic  and  the  care  required  in  the  Dakin-Carrel  treatment. 
It  is  employed  in  7.5  per  cent,  solution  in  chlorinated  eucalyptol 
and  chlorinated  liquid  petrolatum.  The  oils  are  chlorinated  so 
that  they  will  not  take  up  the  chlorine  of  the  antiseptic,  and  they 
liberate  the  antiseptic  slowly  and  continuously  for  a  period  of 
eighteen  to  twenty-four  hours.  Dichloramin-T  corresponds  with 
the  >NC1  substances  formed  when  Dakin's  solution  is  brought 
in  contact  with  the  exudate  of  wounds.  It  is  non-irritant  to  the 
skin  or  in  the  wound,  and,  according  to  Dakin,  is  as  effective  a 
germicide  as  iodine  without  its  destructive  effect.  Like  Dakin's 
solution,  dichloramin-T  can  dissolve  dead  tissue  and  clots,  so  all 
hemorrhage  must  be  stopped  by  ligation. 

Chlorazene  is  a  proprietary  preparation  of  the  sodium  salt  of 
toluene  parasulphochloramin,  a  non-irritant  germicide  four  times 
the  strength  of  phenol  and  used  in  2  per  cent,  solution. 

Bromine  is  a  reddish-brown,  corrosive  liquid,  the  fumes  from 
which  are  very  irritating  to  the  respiratory  passages.  Severe 
bronchitis  and  laryngitis  have  occurred  from  the  breaking  of  a 
bottle  of  bromine  or  its  use  in  the  laboratory.  For  bromine 
burns  the  best  antidote  is  phenol,  which  forms  the  comparatively 
harmless  tribromphenol.  Bromine  water  is  employed  as  a 
gargle. 

Iodine  is  used  in  the  form  of  the  tincture  of  iodine  (iodine, 
7  per  cent.;  potassium  iodide,  5  per  cent.)  in  the  treatment  of 
ring-worm  and  other  parasitic  skin  diseases.  This  tincture 
or  an  alcoholic  solution  free  from  potassium  iodide  has  recently 
come  into  extensive  use  as  a  skin  disinfectant  preliminary  to 
operation.  It  is  highly  convenient  in  preparing  the  skin  for 
paracentesis  and  small  cuts,  and  for  major  surgery.  It  does  not 
injure  the  skin,  and  its  staining  soon  disappears.  Experiments 
have  shown  it  to  have  an  almost  instantaneous  destructive  effect 
upon  the  Staphylococcus  albus  of  the  skin  as  well  as  on  other 
bacteria.  The  work  of  Post  and  Nicoll  (see  Table),  Kinnaman, 
and  many  others  has  established  its  positive  disinfectant  value 


METALS   AND   THEIR   COMPOUNDS  499 

in  surgery.  Kinnaman  found  that  a  i  :  100  iodine  solution  de- 
stroyed the  Bacillus  tuberculosis  in  seven  minutes,  and  Bacillus 
prodigiosus  and  anthrax  bacillus  with  spores  in  ten  minutes. 
Lambert  found  that  among  a  number  of  antiseptics  iodine  was 
the  only  one  to  which  animal  cells  were  more  resistant  than 
staphylococci.  Churchill's  tincture  (16.5  per  cent,  of  iodine) 
is  also  employed,  but  such  strong  solutions  are  not  necessary. 
E.  McDonald  recommends  a  2  per  cent,  solution  in  carbon 
tetrachloride. 

The  antiseptic  iodine  compounds  are  iodoform  and  certain 
iodine-containing  compounds  of  the  phenol  group,  viz.,  thymol 
iodide  (aristol),  europhen  and  losophan,  which  are  cresol  com- 
pounds, and  iodol  (tetra-iodo-pyrrhol) .  These  were  designed 
to  have  the  iodoform  antiseptic  effect  without  its  disagreeable 
odor,  but  they  do  not  act  like  iodoform,  and  are  probably  anti- 
septic because  of  their  phenol  affinities  rather  than  because  of 
their  iodine  constituent.  Their  antiseptic  value  cannot,  there- 
fore, be  judged  by  their  iodine  percentage. 

lodoform  is  a  yellow,  crystalline  powder,  insoluble  in  water, 
and  with  a  disagreeable,  persistent,  and  penetrating  odor.  It 
is  not  germicidal  except  in  contact  with  raw  tissues  or  wound 
secretions,  where  part  of  it  is  believed  to  change  into  iod-albumi- 
nates  and  di-iodo-di-acetylene.  Locally  it  is  irritant  and  may 
cause  a  dermatitis  or  a  pustular  rash.  After  absorption  it  may 
have  simply  the  action  of  an  iodide,  or  give  poisonous  symptoms 
which  indicate  the  presence  of  unchanged  iodoform  in  the  blood, 
lodoform  poisoning  usually  manifests  itself  in  one  of  three  forms, 
the  prominent  symptoms  being — (i)  Vomiting;  (2)  cerebral 
excitement  and  delirium;  or  (3)  cerebral  depression  with  melan- 
cholia. In  each  case  the  outcome  may  be  coma  and  collapse. 
The  poisoning  is  usually  due  to  the  packing  of  large  cavities  with 
strong  iodoform  gauze.  The  symptoms  of  hyperthyroidism 
have  been  reported.  In  tuberculous  sinuses  and  in  the  peritoneal 
cavity  in  tuberculous  peritonitis,  a  mixture  of  iodoform,  glycerin, 
and  ether,  incorrectly  called  "iodoform  emulsion,"  seems  to  be 
of  benefit;  though  the  belief  that  iodoform  exerts  a  specific 
effect  upon  the  tubercle  bacillus  has  no  experimental  support. 
It  has  also  been  thought  to  have  a  special  value  in  infections  by 
the  Bacillus  pyocyaneus.  To  remove  the  odor  of  iodoform  from 
the  hands  Ricketts  recommends  vinegar. 

V.  METALS   AND    THEIR    COMPOUNDS 

These  combine  chemically  with  albumin  to  form  precipitates 
of  metallic  albuminates,  which  make  an  impenetrable  pellicle. 


500  PHARMACOLOGY   AND    THERAPEUTICS 

Thus  the  metallic  salts  have  little  penetrating  power,  and  are 
readily  destroyed  by  the  body  fluids. 

Those  most  employed  as  antiseptics  and  disinfectants  are: 

Of  mercury — mercuric  chloride   and  mercurophen;    also, 

slightly,  in  ointment  form,  ammoniated  mercury  and 

mercuric  oxide. 

Of   gold — sodium    aurate,    reported    by   Verhoeff    (1906) 

as  of  great  efficacy  and  little  toxicity. 
Of  silver — the  nitrate,  protargol,  argyrol,  etc. 
Of  copper  and  iron — the  sulphates. 
Of  zinc — the  sulphate  and  the  chloride. 
Of  aluminium — the  acetate,  made  fresh  in  solution. 
Of    bismuth — the    subiodide,    and    perhaps    slightly    the 

subnitrate  and  other  salts. 
The  pharmacology  of  the  metals  is  considered  further  on. 

VI.  MISCELLANEOUS   INORGANIC   COMPOUNDS 

Potassium  nitrate  (niter  or  saltpeter),  sodium  chloride, 
sodium  borate  (borax),  and  boric  acid  are  employed  as  food 
preservatives,  as  in  corned  beef,  ham,  butter,  etc.  Wiley  says 
that  the  small  quantities  of  salt  in  butter  are  not  preservative. 

Boric  acid,  a  crystalline  solid,  is  soluble  in  18  parts  of  water, 
16  of  alcohol,  and  5  of  glycerin,  and  volatilizes  when  its  solution 
is  boiled.  It  is  soothing  locally,  and  mildly  antiseptic.  Post 
and  Nicoll  (1907)  obtained  no  essential  germicidal  effect  in 
twenty  hours  from  saturated  aqueous  solutions;  but  Bernstein 
(1910)  has  demonstrated  that  it  has  some  power  to  check  the 
growth  of  yeasts  and  harmless  saprophytes,  though  only  slight 
effect  on  typhoid  and  other  pathogenic  germs.  It  is  more 
effective,  therefore,  as  a  preservative  than  as  a  disinfectant. 
About  the  body  it  possibly  acts  more  by  changing  the  reaction  of 
the  fluids  than  by  directly  retarding  the  microbic  growths. 

Its  solution  is  used  extensively  as  a  cleansing  application 
to  inflamed  mucous  membranes,  as  of  the  eye,  nose,  mouth, 
vagina,  etc. ;  its  ointment,  as  an  application  to  eczematous  areas, 
fungous  skin  diseases,  and  burns;  and  the  acid  itself  as  a  dusting- 
powder  in  the  shoes  in  sweating  of  the  feet.  It  is  almost  specific 
against  thrush  in  the  mouths  of  infants.  With  salicylic  acid  it 
forms  the  antiseptic  wash  "boro-sal"  or  Thiersch's  solution,  which 
consists  of  boric  acid,  8 ;  salicylic  acid,  2 ;  and  water,  to  make  1000. 
For  children  it  has  a  wide  range  of  application.  Boric  acid  and 
its  alkaline  salt,  sodium  borate  or  borax,  are  very  widely  em- 
ployed as  food  preservatives.  Borax  was  recommended  by 
Cowers  in  epilepsy  in  doses  of  20  grains  (1.3  gm.)  three  times  a 
day. 


PHENOL   COMPOUNDS  50 1 

Toxicology. — Boric  acid  has  been  the  cause  of  a  number  of 
cases  of  poisoning,  the  symptoms  being:  gastro-enteritis  with 
vomiting  and  diarrhea,  a  papular  eruption  on  the  skin,  general 
edema,  a  gray  line  on  the  gums,  and  central  depression  leading 
to  collapse.  Best  (1904)  gathered  from  the  literature  5  cases 
of  severe  poisoning  and  5  deaths.  Severe  symptoms  have  re- 
sulted from  irrigating  the  colon  with  boric-acid  solution,  from 
packing  the  vagina,  the  ankle-joint,  etc.,  with  the  powder,  from 
washing  out  the  pleural  cavity,  a  lumbar  abscess,  etc.  Recovery 
is  reported  of  an  infant  of  eight  weeks  after  2  doses  of  3  ounces 
(90  c.c.)  of  a  saturated  solution,  part  of  which  was  vomited.  The 
treatment  is  abundance  of  water  and  alkalies. 

The  glycerite  of  boroglycerin,  a  thick  liquid  made  of  boric 
acid  and  glycerin,  is  used  on  vaginal  tampons  in  chronic  endome- 
tritis  and  pelvic  inflammations. 

VII.  PHENOL    COMPOUNDS 

This  group  includes  phenol,  the  sulphocarbolates,  resorcinol, 
pyrogallol,  benzoic  acid,  salicylic  acid,  salol,  cinnamic  acid, 
cresol,  creosol,  guaiacol,  creosote,  tar,  oil  of  cade,  many  volatile 
oils,  camphor,  thymol,  aristol  (di-thymol  di-iodide),  europhen 
and  losophan  (iodine  compounds  of  cresol),  iodol  (tetra-iodo- 
pyrrhol),  naphthalene,  beta-naphthol,  trimethol,  etc. 

The  drugs  of  this  group,  when  taken  internally,  tend  to  in- 
crease the  ethereal  sulphates  of  the  urine,  and  in  some  cases  may 
result  in  indicanuria.  They  are  less  affected  than  most  anti- 
septics by  organic  matter.  They  are  all  antiseptic,  antipyretic, 
and  analgesic.  Their  toxic  action  manifests  itself  by  depression 
of  the  respiratory  and  vasoconstrictor  centers,  coma,  and  collapse. 

Benzoic  and  cinnamic  acids  and  their  salts  are  similar  to 
salicylic  acid  in  their  action,  though  less  effective  in  rheumatism. 
They  are  used  as  food  preservatives,  and  even  in  very  minute 
quantities  retard  the  activity  of  the  digestive  ferments  (Sailer 
and  Farr).  The  cinnamates  have  been  employed  in  tuberculosis. 
Sodium  benzoate  is  used  in  cystitis  to  acidify  and  disinfect  the 
urine.  Dakin  states  that  in  men  amounts  of  i  to  i^  drams 
(4-10  gm.)  daily  for  two  or  three  days  are  practically  all  elimi- 
nated as  hippuric  acid.  Balsam  of  Peru,  which  contains  ben- 
zoates  and  cinnamates,  is  used  externally  in  chronic  skin  diseases; 
and,  in  the  form  of  "balsam  gauze,"  is  applied  to  ulcers  or  wounds 
as  a  stimulant  of  granulation. 

Benzoin,  which  is  also  a  balsam  containing  benzoates  and 
cinnamates,  is  very  fragrant.  It  is  employed  for  inhalation  in 
whooping-cough,  laryngitis,  nasopharyngitis,  bronchitis,  and 


502 


5     £ 
:/-\ 

O 

a 

u 
o 


PHARMACOLOGY  AND   THERAPEUTICS 

a 


Creosol 


IK     Sodium  Phenol 
O     Sulphonate 
(Ethereal  Sul- 
phate) 


O 

4 

' /      \ 

<Q  y>w    Sulpho 


a 


/  —  \8 

U     ^nmVAc 


\         /         (Inactive  and 

passes  unchanged) 


icarbolate       ^ 


U 

<^  yCresol 


O 

u 
5   a 


Phenacetin 


IPhloroglucin 
(not  antiseptic) 


O        O 


Salicylic 

Add 


O 

Benzoic      O 
Acid         U 

a 

u 
H 

I  a 

Pyro-         ° 
gallol 


>O  Hydro- 
quinone 


>Resorci- 
nol 


I  Pyro-          ° 
catechin 

Phenol 

a 
u 

Benzol       ° 


O 
U 

3   a 
\/ 


Acetanilid 


'Cinnamic  Acid 


Thymol 


Eugenol 


'Anisol 


O 

Thymol 
_,     Iodide 

O 


Guaiacol 
Carbonate 


*U  Trichlor- 
phenol 


Europhcn  =  Cresol  iodide. 
Losophan  =  Tri-iodo  cresol. 


(Tetra- 

iodo- 

pyrrhol) 


Beta- 


Naphtalin 


/Antinosine  =  Na  salt. 
vEudoxine  =  Bi  salt. 
The  Chemical  Relationships  of  the  Phenol  Group  of  Disinfectants. 


Nosophen  =  Tetra-iodo-phenolphthalein< 

x- 


PHENOL    COMPOUNDS  503 

pneumonia,  one  teaspoonful  of  the  compound  tincture  (benzoin, 
aloes,  storax,  and  tolu)  being  added  to  boiling  water  in  a  pitcher 
or  to  water  boiling  in  a  croup-kettle,  and  the  steam  inhaled. 
Its  tincture  is  also  mixed  with  water  and  used  as  a  lotion  for 
the  skin  in  ivy-poisoning,  sunburn,  and  other  forms  of  dermatitis. 

Creosote,  which  is  an  empyreumatic  volatile  oil  obtained 
during  the  distillation  of  wood-tar,  contains  70  to  80  per  cent, 
of  guaiacol  with  cresol  and  creosol.  A  few  drops  may  be  used 
with  steam  in  the  same  conditions  as  the  compound  tincture 
of  benzoin,  or  it  may  be  dropped  on  the  sponge  of  a  zinc  respi- 
rator. Because  of  its  strong  odor,  it  is  employed  as  an  inhalant 
in  ozena,  fetid  bronchitis,  tuberculosis,  bronchiectasis,  gangrene 
of  lung,  etc.  Internally,  its  chief  employment  is  in  pulmonary 
tuberculosis  or  persistent  bronchitis,  in  dose  of  5  minims  (0.3  c.c.). 
It  is  very  irritant  to  many  stomachs  and  disagreeable  to  the 
taste,  but  it  can  often  be  taken  in  milk  or  cod-liver  oil,  or  with  a 
strong  tasting  tincture,  such  as  the  compound  tincture  of  gen- 
tian. In  some  cases  of  tuberculosis  it  has  a  good  effect  on  appe- 
tite, fever,  and  night-sweats.  It  is  excreted  to  some  extent  by 
the  lungs,  as  noticed  in  the  breath  and  sputum,  but  there  is  no 
evidence  of  any  antiseptic  value  in  tubercle  tissue  or  in  the 
bronchi.  Creosote  carbonate  (the  carbonic  ester)  is  a  liquid  of 
less  penetrating  odor  and  less  biting  taste,  and  it  may  be  odor- 
less and  tasteless. 

Guaiacol,  the  chief  constituent  of  creosote,  is  an  oily  liquid, 
and  is  used  in  the  same  way  as  creosote;  dose,  5  minims  (0.3  c.c.). 
It  is  also  employed  as  a  counterirritant  in  epididymitis  and  tuber- 
culous peritonitis.  Guaiacol  carbonate  (the  carbonic  ester)  is  a 
solid,  and  is  given  in  5-grain  (0.3  gm.)  capsules.  It  is  tasteless 
and  odorless  and  is  usually  well  borne  by  the  stomach. 

Cresol  is  much  more  germicidal  than  phenol.  Compound 
cresol  solution  (liquor  cresolis  compositus)  consists  of  50  per  cent, 
of  cresol  in  a  solution  of  soft  soap.  It  is  used  in  i  per  cent,  solu- 
tion in  water.  Proprietary  remedies  of  similar  nature  are  lysol 
and  creolin.  Fatal  poisoning  has  several  times  resulted  from 
confusion  over  the  name  lysol.  At  the  Hygienic  Laboratory 
the  disinfecting  value  in  inorganic  solutions  as  compared  with 
phenol  was,  for  compound  cresol  solution,  3;  for  creolin,  3.25;  for 
lysol,  2.12.  In  solutions  of  peptone  and  gelatin,  the  value  for 
compound  cresol  solution  was  1.87;  for  creolin,  2.52;  and  for 
lysol,  1.57. 

Resorcinol  (resorcin),  readily  soluble  in  water  and  alcohol, 
is  used  in  10  per  cent,  solution  as  a  scalp  wash  for  dandruff, 
and  in  skin  lotions  as  antiseptic  and  antipruritic.  In  the  stomach 
it  is  antifermentative;  dose,  5  grains  (0.3  gm.).  A  number  of 


504  PHARMACOLOGY   AND   THERAPEUTICS 

cases  of  poisoning  are  reported,  even  from  the  application  of  an 
ointment. 

Pyrogallol  turns  brown  on  exposure  to  air.  It  is  employed 
in  fungous  skin  diseases.  Tar  and  oil  of  cade  are  added  to  oint- 
ments for  chronic  eczema  and  ring-worm.  The  syrup  of  tar 
(syrupus  picis  liquidac)  is  used  in  bronchitis  as  an  expectorant. 
Naphthalin  and  beta-naphthol  have  a  questionable  value  as 
intestinal  antiseptics;  dose,  5  grains  (0.3  gm.).  Fatalities 
are  reported  from  a  dose  of  1.75  gm.  of  naphthalin  given  for 
thread-worms,  and  from  moth-balls  eaten  by  children.  Tri- 
methol  (trimethyl-methoxy-phenol),  a  proprietary  remedy  pro- 
posed as  an  intestinal  disinfectant,  is  given  in  capsule  or  tablet  in 
doses  of  about  20  a  day.  It  may  be  irritant  to  the  stomach.  For 
children  a  syrup  is  obtainable.  The  iodine  phenol  compounds 
are  probably  antiseptic  rather  in  relation  to  their  phenol  constit- 
uent than  to  their  iodine ;  they  were  brought  out  as  substitutes  for 
iodoform.  Thymol  iodide  (aristol)  is  much  employed  as  an  anti- 
septic dusting-powder. 

Volatile  Oils. — Eucalyptol  is  one  of  the  strongest  antiseptics 
in  the  volatile  oil  group,  but,  owing  to  its  oily  nature,  cannot 
readily  be  employed  as  an  antiseptic.  Its  chief  use  is  as  an 
inhalant  in  respiratory  diseases,  coryza,  whooping-cough,  bron- 
chitis, etc.,  either  with  steam  or  by  respirator,  or  sprayed  from 
an  atomizer.  A  favorite  spray  consists  of  about  2  per  cent, 
each  of  eucalyptol,  camphor,  and  menthol,  dissolved  in  liquid 
paraffin.  An  application  for  burns  is  gauze  impregnated  with 
paraffin  containing  eucalyptol  and  other  aromatic  disinfectants. 
Oil  of  cinnamon,  oil  of  cloves,  and  cugenol  are  used  by  dentists. 

Antiseptic  solution  (liquor  antisepticus,  N.  F.)  has  been 
shown  to  have  very  slight,  if  any,  antiseptic  power.  Its  chief 
use  is  as  a  pleasant  mouth-wash,  and  it  is  an  official  substitute 
for  a  number  of  proprietaries  incorrectly  called  antiseptic,  and 
aptly  dubbed  by  Sollmann  the  "psychic  antiseptics."  For  in- 
gredients, see  page  489. 

PHENOL,    OR    CARBOLIC   ACID 

Phenol  is  made  synthetically  and  is  also  obtained  from  coal-tar 
by  fractional  distillation.  It  is  a  crystalline  substance,  of  faintly 
acid  reaction,  freely  soluble  in  alcohol,  glycerin,  and  the  oils,  and 
in  20  parts  of  water.  The  crystals,  which  consist  of  about  96  per 
cent,  of  pure  phenol,  melt  on  warming,  and  remain  liquid  on  the 
addition  of  about  8  to  10  per  cent,  of  water.  The  official  "phenol 
liquefactum"  is  made  by  adding  10  parts  of  water  to  90  parts 
of  the  crystals.  This  forms  a  stock  solution  which  is  easier  to 
handle  than  the  crystals  regularly  employed;  but  if  water  is 


PHENOL,   OR   CARBOLIC   ACID  505 

added  to  it,  the  phenol  separates  as  an  oily  liquid,  and  does  not 
go  into  solution  again  until  about  20  times  its  weight  of  water  has 
been  added.  In  other  words,  one  can  make  a  solution  of  official 
phenol  of  5  per  cent,  or  90  per  cent,  strength,  but  not  of  any 
strength  between.  If,  however,  the  phenol  is  previously  dis- 
solved in  glycerin,  it  can  be  mixed  in  any  proportion  with 
water.  Phenol  precipitates  albumin,  gelatin,  and  collodion,  and 
makes  a  violet  color  with  ferric  salts. 
Preparations.— 

Phenol,  96  per  cent,  pure  phenol  in  crystal  form. 
Liquefied  phenol  (phenol  liquefactum) — a  permanent  liquid 
made  by  mixing  9  parts  of  phenol  crystals  with  i  of 
water. 
Ointment,  3  per  cent,  in  white  petrolatum.     Phenol  tends 

to  separate  out  on  long  standing. 
Glycerite,  a  20  per  cent,  solution  in  glycerin. 
Dobell's  solution  (liquor  sodii  boratis  compositus,  N.  F.), 
which  contains  0.3  per  cent,  of  phenol  and  1.5  per  cent, 
each  of  sodium  bicarbonate  and  borax,  with  glycerin 
and  water. 

Pharmacologic  Action. — Microorganisms. — Phenol  exerts  a 
powerful  precipitating  effect  upon  protoplasm.  This  precipitate 
is  not  due  to  chemic  combination,  but  to  change  of  solvent,  i.  e., 
the  protoplasmic  elements  are  insoluble  in  a  solution  of  phenol. 
There  is  no  chemic  action,  and  the  phenol  can  be  washed  out 
of  the  tissues  by  a  solvent.  Since  it  is  not  chemically  combined, 
it  has  greater  penetrating  power  than  most  of  the  disinfectants. 
Even  very  dilute  solutions,  i  :  500,  cause  the  prompt  cessation 
of  motion  of  protozoa,  leukocytes,  spermatozoa,  and  ciliated 
epithelium,  the  protoplasm  of  the  cell  becoming  granular  and 
the  cell  soon  disintegrating. 

Bacteria,  as  they  have  a  cell  wall,  are  more  resistant;  yet 
even  these  are  penetrated  more  readily  by  phenol  than  by  most 
germicides.  The  susceptibility  to  the  phenol  varies  greatly 
with  the  different  kinds  of  bacteria,  and  the  spores  are  so  resistant 
that  they  require  to  be  exposed  to  strong  solutions  for  hours. 
Wilbert  (1916)  shows  that  a  mixture  of  i  per  cent,  of  phenol  and 
9  per  cent,  of  alcohol  with  water  is  distinctly  more  disinfectant 
than  a  i  per  cent,  solution  of  phenol  in  water  alone.  A  solution 
in  oil  has  diminished  antiseptic  action;  for  the  phenol  has  greater 
affinity  for  oil  than  for  the  water  or  solution  of  salts  in  the  tissues, 
and  consequently  does  not  penetrate  into  the  organism.  A  5 
per  cent  carbolic  ointment  made  with  lard  will  go  rancid  in  spite 
of  the  antiseptic. 

Very  dilute  solutions  tend  to  activate  both  unorganized  and 


506  PHARMACOLOGY   AND   THERAPEUTICS 

organized  ferments;  stronger  solutions  retard  their  activity,  and 
especially  diminish  that  of  the  unorganized  ferments  of  the  ali- 
mentary tract. 

Locally,  phenol  is  somewhat  anesthetic,  tending  to  allay 
itching  and  pain.  It  is  absorbed  by  the  unbroken  skin,  but  much 
more  readily  by  mucous  membranes,  and  it  acts  on  the  sensory 
nerve-endings  to  produce  numbness,  though  not  complete 
analgesia.  There  may  also  be  tingling.  This  may  occur  from 
i  to  5  per  cent,  solutions,  as  when  the  hands  are  kept  wet  with 
a  solution  in  its  surgical  use.  It  thus  may  considerably  lessen 
pain,  but  usually  does  not  annul  it.  The  tingling  and  numb- 
ness may  last  half  an  hour  or  more.  Strong  phenol  produces 
a  burn,  the  pain  from  which  is  sometimes  not  noticeable  at  first 
on  account  of  the  anesthetic  action.  The  skin  becomes  white 
and  cold  from  constriction  of  the  vessels,  and  numb  from  paral- 
ysis of  the  ends  of  the  sensory  nerves;  later  it  becomes  red  and 
very  painful,  and  still  later  may  dry  up  and  peel  off,  or  the 
superficial  tissues  may  slough  off  and  leave  a  painful,  slowly  heal- 
ing, ulcerated  area. 

Both  weak  and  strong  solutions  applied  to  a  finger  or  toe  as 
wet  dressings  have  frequently  resulted  in  gangrene,  the  carbolic 
slowly  penetrating  the  tissues  and  causing  their  death,  while 
the  anesthetic  effect  prevents  the  warning  of  pain.  After  a  few 
hours  the  finger  is  found  to  be  white  and  dead,  and  it  subse- 
quently turns  black  on  the  surface.  It  is  sometimes  necessary 
to  amputate,  but  usually  not.  Strong  phenol  usually  causes 
pain  early,  so  that  measures  are  taken  to  stop  the  action,  hence 
gangrene  is  less  likely  than  from  weak  solutions. 

When  applied  to  a  wound,  phenol  solutions  coagulate  the 
blood  and  protein  matters  and  form  a  pellicle  over  the  surface. 
This  pellicle  protects  the  germs,  so  that  phenol  may  have  an 
undesirable  effect  upon  the  body  cells  and  no  useful  one  on  the 
bacteria. 

On  mucous  membranes  there  are  the  same  anesthetic  and 
corrosive  actions  as  on  the  skin.  Weak  solutions  in  the  stomach 
are  somewhat  anesthetic  and  may  allay  vomiting. 

Systemically,  phenol  resembles  acetanilid  in  its  action,  but 
the  antiseptic  and  collapse  actions  predominate,  and  the  anti- 
pyretic action  is  less.  At  first  the  heart  is  stronger  from  direct 
stimulation  of  its  muscle;  later  this  is  weakened.  The  vaso- 
constrictor and  respiratory  centers  are  also  at  first  stimulated, 
then  markedly  depressed,  and  in  fever  the  temperature  is  lowered. 
But  collapse  is  readily  produced,  and  because  of  this  the  drug  is 
not  employed  for  its  systemic  effect.  We  must  understand  these 
effects,  however,  because  of  the  frequency  of  carbolic  poisoning. 


Fig.  63  .-Carbolic-acid  poisoning.     Coagulation  of  crests  of  the  folds  of  mucos-. 
in  the  stomach  (MacCallum). 


PHENOL,  OR  CARBOLIC  ACID  507 

In  a  study  of  the  effects  of  the  products  of  intestinal  putre- 
faction on  muscle,  F.  S.  Lee  found  that  in  a  solution  of  phenol, 
i  :  2000,  a  muscle  did  nearly  twice  as  much  work  as  before,  while 
in  solutions  of  i  :  1000  the  muscle  readily  became  fatigued  and 
did  less  work  (Herter). 

Excretion  is  by  the  urine.  The  phenol  passes  out  partly 
unchanged  and  partly  oxidized  to  hydroquinone  and  pyrocat- 
echin  in  combination  as  ethereal  sulphates  and  glycuronates. 
The  urine  may  have  a  smoky  or  dusky  appearance,  or  may 
change  to  brownish-black  or  greenish-black  on  exposure  to  the 
air.  In  poisoning,  practically  all  the  sulphates  of  the  urine  may 
be  in  the  form  of  ethereal  sulphates,  the  inorganic  sulphates 
completely  disappearing. 

Toxicology. — Phenol  is  usually  readily  obtainable,  and  is 
a  favorite  drug  for  committing  suicide.  Darlington  points  out 
that,  in  New  York  city  alone,  as  the  result  of  an  ordinance 
forbidding  the  sale  of  strong  carbolic,  the  number  of  suicides 
fell  from  343  in  a  year  to  36.  Its  recognition  is  usually  easy 
from  the  odor,  the  corroded  tongue  and  mouth  covered  with 
white  pellicle,  and  the  empty  bottle.  A  case  of  fatal  poisoning 
occurred  from  a  surgical  dressing  at  St.  Thomas'  Hospital, 
London. 

The  effects  from  a  poisonous  dose  may  be  of  three  types: 

1.  After   an   overwhelming   dose   the   victim   becomes   un- 
conscious almost  immediately  and  dies  in  a  few  minutes  from 
shock. 

2.  From    good-sized   but    not   immediately    fatal    doses    of 
strong  phenol  the  local  corrosion  is  marked,  and  there  is  rapid 
absorption  of  a  large  quantity  of  the  drug.     The  patient  is  found 
in  collapse,  perhaps  unconscious,  with  muscular  tremors  and 
twitchings  or  rarely  convulsions.     Death  may  follow  in  a  few 
hours  from  paralysis  of  the  respiration,  the  patient  never  regaining 
consciousness.     Or   recovery  may  take   place,   with   extensive 
corrosion   of    the   mouth,    pharynx,    esophagus,    and   stomach. 
Perforation  of  the  stomach  may  occur,  or  months  later  cicatricial 
contractions  in  any  part  of  the  burned  area,  as  in  the  pharynx, 
esophagus,  and  stomach. 

The  symptoms  of  poisoning  by  strong  phenol  are,  then: 
corrosion  of  the  alimentary  tract,  followed  by  collapse,  coma, 
and  perhaps  convulsions. 

3.  Where  weak  solutions  have  been  taken,  there  is  no  local 
corrosion,  but  there  is  a  gradual  onset  of  collapse  from  depres- 
sion of  centers  and  heart  muscle.     There  are  cold,  clammy  skin, 
nausea,  vomiting,  weak   shallow  breathing,  weak  rapid   pulse, 
mental  depression  and  anxiety,  or  coma   and   prostration,  fol- 


508  PHARMACOLOGY   AND    THERAPEUTICS 

lowed  by  recovery  or  death.  The  sulphates  are  lacking  in  the 
urine,  so  that  when  barium  chloride  does  not  give  a  precipitate 
in  the  urine,  it  is  a  fair  conclusion  that  the  patient  is  poisoned 
with  phenol. 

Phenol  is  the  most  frequent  cause  of  ochronosis  (Beddard). 

Treatment  of  Poisoning. — i.  Locally,  to  remove  the  phenol, 
the  best  application  is  alcohol.  But  a  bland  oil  or  fat  (olive, 
cottonseed,  or  linseed  oil,  or  lard  or  butter),  or  glycerin  or  vine- 
gar will  serve.  These  have  more  solvent  powers  for  carbolic 
than  the  liquids  of  the  protoplasm, 'so  tend  not  only  to  prevent 
penetration,  but  also  to  extract  the  carbolic  from  the  tissues. 
For  the  stomach,  whisky  or  a  20  per  cent,  solution  of  alcohol 
may  be  employed;  but  this  must  be  washed  out  at.  once,  as  the 
alcoholic  solution  of  phenol  is  very  readily  absorbed,  and  alcohol 
does  not  prevent  the  systemic  effects.  Clarke  and  Brown  have 
shown  that  lavage  with  water  is  an  effective  measure.  It  is- 
said  that  lime  will  form  an  insoluble  compound,  and  that  potas- 
sium permanganate  will  oxidize  and  destroy  the  phenol,  but  these 
substances  can  hardly  be  given  in  sufficient  quantity.  After 
thorough  lavage  with  water  or  3  per  cent,  sodium  sulphate, 
demulcents,  such  as  oils,  milk,  and  white  of  egg,  may  be  swallowed. 
The  burns,  ulcers,  or  cicatricial  contractions  must  later  on  be 
treated  like  any  other  burns  or  ulcers  or  cicatrices. 

2.  Systemically. — On  account  of  the  disappearance  of  the 
inorganic  sulphates  from  the  urine  and  their  replacement  by 
ethereal  sulphates,  it  has  been  believed  that  the  alkaline  sul- 
phates would  combine  with  the  phenol  to  form  non-toxic  sulpho- 
carbolates  (phenolsulphonates),  and  so  lessen  its  activity  and 
promote  its  excretion.  (The  phenolsuphonates  are  not  formed 
in  a  test-tube  or  in  the  stomach,  though  they  are  slowly  formed 
in  the  body.)  On  this  theory  sulphates  have  been  given  by 
mouth  in  carbolic  poisoning,  and  sodium  sulphate  in  i  to  2  per 
cent,  solution  has  been  administered  intravenously.  Sollmann 
and  Brown  (1907)  studied  this  matter  very  carefully  by  an 
extended  series  of  experiments,  and  found  that  the  combination 
takes  place  too  slowly  for  any  useful  antidotal  effect,  whether 
the  sulphates  are  given  before,  with,  or  after  the  phenol,  and 
whether  they  are  given  by  mouth  or  intravenously;  therefore  they 
are  not  chemic  antidotes.  A  saline  infusion  may,  however,  be 
of  great  value  in  the  treatment  of  collapse  and  to  promote  diu- 
resis; and  it  would  be  well  to  add  i  per  cent,  of  sodium  sulphate 
to  this.  The  treatment  is  that  for  collapse. 

Therapeutics.- — Locally,  phenol  is  added  to  lotions  to  allay 
itching.  Strong  phenol  is  used  as  a  powerful  local  antiseptic  in 
clog-bite,  carbuncles,  small  infected  cavities,  and  other  small 


MISCELLANEOUS    ORGANIC   COMPOUNDS  509 

superficial  wounds.  Its  continued  action  or  penetration  may 
be  checked  by  alcohol.  It  is  sometimes  injected  into  cyst  cavities 
to  cause  an  inflammation  and  obliteration  of  the  cyst  (bursitis, 
hydrocele),  and  also  into  hemorrhoids. 

For  ordinary  antiseptic  purposes,  as  washing  a  wound,  disin- 
fecting excreta,  towels,  bedding,  etc.,  solutions  of  i  to  5  per  cent, 
strength  are  employed  for  from  one-half  to  two  hours.  They 
are  more  antiseptic  and  more  penetrating  than  the  ordinary 
solutions  of  bichloride  of  mercury,  and  they  do  no  harm  to 
fabrics  or  metal  dishes.  In  the  European  war  Chlumsky's 
Solution  has  been  much  employed.  It  consists  of  phenol,  30 
parts;  camphor,  60;  alcohol,  10. 

Bacelli  (1911)  tabulates  94  cases  of  tetanus  treated  intraven- 
ously by  increasing  doses  of  5  to  22^  grains  (0.3-1.5  gm.),  in 
twenty-four  hours,  in  a  2  per  cent,  solution.  He  found  that  in 
190  reported  cases  the  mortality  was  only  17.36  per  cent.  The 
method  would  seem  to  be  highly  dangerous;  but  Bacelli  thinks 
that  patients  with  tetanus  are  exceptionally  tolerant  to  phenol. 

VIZI.  MISCELLANEOUS   ORGANIC   COMPOUNDS 

Ichthyol.  and  thiol  are  oily-looking  sulphur  compounds  which 
are  soluble  in  water  and  the  oils,  and  not  in  alcohol.  Ichthyol 
is  obtained  from  a  shale,  and  thiol  is  prepared  synthetically. 
Their  3  to  5  per  cent,  solutions  are  applied  externally  as  soothing 
lotions,  as  in  bad  sunburn.  Their  50  per  cent,  solution  is  painted 
over  infected  areas  to  promote  absorption  of  serous  or  fibrinous 
exudates.  Ichthyol  ointment,  10  to  50  per  cent.,  is  applied  to 
lessen  glandular  or  joint  swellings  and  in  erysipelas.  It  has  been 
thought  that  it  may  favor  the  resistance  of  the  tissues  by  inducing 
a  local  gathering  of  leukocytes.  Vaginal  tampons  bearing  a 
solution  of  10  to  30  per  cent,  in  glycerin  are  largely  employed  in 
cases  of  chronic  endometritis  and  chronic  pelvic  inflammations. 
Ichthyol  has  an  unpleasant  odor,  \vhile  thiol  is  nearly  odorless. 

Internally,  ichthyol  is  employed  in  cases  of  intestinal  putre- 
factive toxemia  as  an  intestinal  disinfectant,  dose,  3  to  5  grains 
(0.2-0.3  S111-)  m  a  capsule  or  enteric  pill.  It  is  slightly  laxative. 
Ichthyol  enters  into  "Bum  Mixture."  (See  Hoffmann's  Ano- 
dyne.) 

Methylene-blue  (methyl-thionine  chloride)  is  little  used  as  an 
antiseptic.  It  turns  the  urine  a  bluish-green,  a  fact  that  has 
been  made  use  of  as  a  functional  test  for  the  kidneys.  It  has 
been  injected  into  recurrent  or  inoperable  carcinomata,  but  with- 
out any  noteworthy  effects.  After  its  ingestion  by  mouth 
Brauer  found  large  quantities  of  it  in  the  bile.  The  ordinary 


510  PHARMACOLOGY  AND  THERAPEUTICS 

commercial  article  usually  contains  zinc,  and  if  taken  internally 
may  cause  vomiting.  The  author  saw  a  case  of  acute  gastro- 
enteritis follow  a  capsule  of  methyl-blue,  prescribed  by  the 
physician  in  mistake  for  methylene-blue. 

Formaldehyd  (HCOH)  is  a  gas,  and  its  aqueous  solution, 
containing  not  less  than  37  per  cent,  by  weight  of  absolute 
formaldehyd,  is  official  under  the  name  of  "Liquor  Formalde- 
hydi."  This  solution  should  be  neutral  or  only  faintly  acid 
to  litmus,  showing  the  absence  of  formic  or  other  acids.  It  is 
marketed  under  the  name  of  "Formalin,"  and  usually  contains 
about  10  per  cent,  of  methyl  alcohol  to  facilitate  solution  and 
prevent  polymerization.  At  ordinary  temperature  it  gives  off 
formaldehyd  gas.  On  cooling  the  solution  below  68°  F.,  a  white 
powder  results.  This  is  known  as  paraformaldehyd  (paraform, 
trioxymethylene) ,  and  is  a  polymeric  form  of  formaldehyd.  On 
gently  heating,  this  is  reconverted  into  gaseous  formaldehyd. 

Formaldehyd  is  pungent  and  very  irritating  to  eyes,  nose, 
and  throat.  It  is  rendered  inert  by  alkalies,  especially  ammonia ; 
it  reduces  Fehling's  solution;  it  attacks  metals  (instruments); 
it  hardens  tissues,  blood,  and  gelatin  (blood  on  the  hands  be- 
comes darkened  and  difficult  to  wash  off) .  This  last  property  has 
been  made  use  of  to  harden  gelatin  capsules  so  that  they  would 
pass  through  the  stomach  into  the  intestine  before  dissolving 
(glutol  capsules);  but  the  degree  of  hardening  is  uncertain. 
It  is  employed  as  a  hardening  and  fixing  agent  for  anatomic 
and  biologic  specimens,  and  is  used  as  an  arterial  injection  for 
embalming  the  dead  and  for  preserving  cadavers  for  dissection. 
It  may  be  employed  for  fixing  blood-smears.  An  important 
property  is  that  of  preventing  the  coagulation  of  serum  albumin 
by  heat,  as  in  urine. 

Formaldehyd  is  a  powerful  disinfectant.  It  is  much  employed 
as  a  preservative  of  foods.  One  part  in  20,000  cannot  be  detected 
by  its  odor,  yet  will  keep  milk  for  several  days.  In  i  :  50,000 
strength  it  retards  the  growth  of  the  lactic  acid  bacillus,  but  has 
little  effect  on  the  colon  or  typhoid  bacillus  (Vaughan).  Bur- 
nam  (1912)  found  that  a  i  :  20,000  solution  retarded,  but  did 
not  destroy,  typhoid  bacillus  and  streptococcus;  but  that  a 
i  :  1000  solution  killed  colon,  typhoid,  and  pyocyaneus  bacilli, 
streptococcus  and  Staphylococcus  aureus  in  twenty-four  hours. 
It  is  used  as  a  preservative  of  cider,  fruit-juices,  and  canned  foods, 
and  is  employed  as  a  valuable  general  disinfectant  for  sick-rooms. 

The  gas  may  be  generated — (i)  By  warming  the  solution  ;  (2) 
by  heating  paraformaldehyd;  (3)  by  adding  one  pound  of  fresh 
quicklime  to  a  mixture  of  6  ounces  of  aluminium  sulphate  and 
8  ounces  of  formaldehyd  solution,  as  advised  by  the  New  York 


MISCELLANEOUS   ORGANIC   COMPOUNDS  51! 

Health  Department,  this  amount  yielding  enough  gas  to  dis- 
infect a  room  containing  1000  cubic  feet;  (4)  but  the  best  method 
of  all  is  to  add  compressed  blocks  of  potassium  permanganate 
to  the  formaldehyd  solution  in  a  large  pail.  The  gas  is  given  off 
with  violent  ebullition  (formanganate  disinf ector) .  (5)  Lawall 
pours  a  mixture  of  i|  ounces  (45  c.c.)  of  commercial  sulphuric 
acid  with  i  pint  (480  c.c.)  of  formaldehyd  solution  over  9  ounces 
(270  gm.)  of  sodium  dichromate  crystals.  This  is  cheaper  than 
the  permanganate  method. 

The  exposure  to  the  gas  should  be  from  twelve  to  twenty-four 
hours.  It  has  little  penetrating  power,  so  may  fail  to  enter  the 
cracks  in  the  floor  or  penetrate  a  mattress.  In  the  presence  of 
moisture,  as  steam,  it  is  more  effective  than  when  dry.  If  the 
temperature  of  the  room  is  below  52°  F.,  it  may  polymerize  into 
paraform.  It  does  not  kill  vermin.  Doty  and  others  report 
that  bedbugs,  roaches,  mosquitos,  or  even  rats,  rabbits,  and 
guinea-pigs  were  alive  after  many  hours'  exposure.  The  gas  is 
immediately  neutralized  by  ammonia  gas. 

Formaldehyd  is  somewhat  used  for  sterilizing  absorbent 
cotton,  sutures,  and  surgical  dressings;  but,  on  account  of  its 
action  on  metals,  its  irritating  vapor,  and  its  bad  effect  on  the 
hands,  is  limited  in  its  use  as  a  surgical  disinfectant. 

Locally,  the  solution  of  formaldehyd  has  been  used  in  fungous 
skin  diseases  (favus,  sycosis,  ring-worm),  to  disinfect  foul  ulcers 
and  cancers,  to  check  local  sweating,  and  to  harden  and  dry  up 
small  growths,  such  as  moles,  condylomata,  and  even  cancer. 
Daniel  says  that  formalin  rubbed  into  warts  with  a  stick  makes 
them  come  off  without  leaving  a  scar.  In  very  weak  solution 
it  has  been  employed  as  an  antiseptic  to  mucous  membranes,  as 
in  catarrh  of  the  nose,  throat,  or  vagina — usually  with  other 
mucous  membrane  antiseptics.  Recently  it  has  been  recom- 
mended to  leave  a  weak  solution  of  formaldehyd  in  the  pleural 
cavity  after  paracentesis  for  pleurisy  with  effusion. 

Poisoning. — There  are  a  number  of  reported  cases  of  poisoning 
from  its  ingestion  by  mouth,  with  intense  irritation  of  the  esoph- 
agus and  stomach,  vomiting,  diarrhea,  coma,  and  collapse.  The 
kidneys  are  also  irritated,  as  shown  by  albuminuria,  bloody  urine, 
or  suppression.  The  urine  may  contain  albumin  and  formic 
acid.  The  chemic  antidote  for  the  stomach  is  ammonia,  well 
diluted,  and  followed  by  demulcents,  such  as  bland  oils,  mucilagin- 
ous drinks,  starch  water,  milk,  and  white  of  eggs.  Collapse  is 
treated  in  the  usual  way. 

4XH3     +     6HCOH     =     X«(CH2)6     +     6H:O 
Ammonia         Formaldehyd  Hexamethyl-  Water 

enamine 


512  PHARMACOLOGY   AND   THERAPEUTICS 

Hexamethylenamine,  N4(CH2)6,  known  also  as  urotropine, 
cystogen,  formin,  etc.,  is  an  artificial  alkaloid  made  by  combining 
6  molecules  of  HCOH  with  4  of  ammonia.  It  occurs  in  crystals 
which  are  soluble  in  1.2  parts  of  water  and  in  10  parts  of  alcohol. 
It  is  incompatible  with  acids  and  salts  of  acid  reaction,  and  with 
mercuric  chloride. 

Hexamethylenamine  has  no  local  action.  A  50  per  cent, 
solution  is  non-irritant  (Burnam).  In  the  acid  gastric  juice 
formaldehyd  is  liberated  and  may  be  irritating.  It  is  rapidly 
absorbed,  has  no  essential  systemic  action,  and  appears  in  the 
urine  in  a  few  minutes.  If  the  kidneys  are  diseased  its  excretion 
is  greatly  retarded,  a  fact  which  explains  the  "urotropin  test" 
for  kidney  function.  It  has  been  found  in  the  ear  discharge  in  a 
case  of  middle-ear  disease,  and  in  the  milk,  bile,  pancreatic  juice, 
blood,  saliva,  synovial  fluid,  nasal  and  bronchial  secretions, 
pleural  effusions,  and  cerebrospinal  fluid  of  human  beings.  It  is 
not  essentially  diuretic,  and  has  no  power  to  dissolve  uric-acid 
calculi.  It  came  into  use  as  a  urinary  disinfectant,  its  value 
depending  on  its  ability  to  liberate  formaldehyd.  This  it  tends 
to  do  in  acid  fluids. 

Jordan  (1911)  gave  10  grains  (0.7  gm.)  three  times  a  day,  and 
found  that  when  the  urine  was  alkaline  or  of  low  acidity,  there  was 
no  germicidal  effect.  When  the  urine  was  alkaline,  he  could 
obtain  the  effect  by  administering  acid  sodium  phosphate  to 
acidify  the  urine;  and  when  the  urine  was  acid,  he  could  lessen 
the  effect  by  administering  potassium  citrate.  Sollmann  (1908) 
found  that  in  alkaline  urine  it  developed  antiseptic  properties, 
i.  e.,  formaldehyd  in  antiseptic  amounts,  only  after  one  and  a  half 
hours.  In  ammoniacal  urine  formaldehyd  cannot  exist,  as  it  has 
great  chemic  affinity  for  ammonia.  When  formaldehyd  is 
present,  the  urine  will  reduce  Fehling's  solution. 

At  Johns  Hopkins  Hospital  hexamethylenamine  was  found  to 
lessen  greatly  the  number  of  typhoid  bacilli  in  the  urine  of  typhoid 
patients,  though  not  to  render  the  urine  completely  germ  free.  In 
pyelitis  and  in  cystitis  it  is  disinfectant,  though  in  Bacillus  coli 
infections  and  in  gonorrhea  it  has  sometimes  failed  completely  to 
clear  the  urine.  L'Esperance  found  formaldehyd  present  in  the 
urine  in  52  per  cent,  of  cases  taking  hexamethylenamine.  Burnam 
(1912)  tested  the  urines  of  some  of  Howard  A.  Kelly's  cases  after 
they  were  given  hexamethylenamine.  Of  10  cases  taking  5  to  10 
grains  (0.3-0.7  gm.)  three  times  a  day,  only  2  showed  formalde- 
hyd; some  others  gave  the  reaction  when  the  dose  was  increased 
to  20  to  30  grains  (1.3-2  gm.)  every  four  or  six  hours;  and  some 
gave  no  reaction,  even  after  a  dose  of  100  grains  (6.7  gm.).  He 
found  it  in  some  cases  with  alkaline  urine,  and  failed  to  get  it  in 


MISCELLANEOUS   ORGANIC   COMPOUNDS  513 

some  with  acid  urine.  In  some  patients  the  concentration  in 
the  urine  reached  as  high  as  i  :  5000.  Levy  and  Strauss  obtained 
similar  results  and  found  this  strength  antiseptic,  but  not 
germicidal,  except  to  the  typhoid  bacillus. 

The  use  of  hexamethylenamine  in  therapeutics  depends  solely 
on  its  power  to  liberate  formaldehyd.  Its  appearance  in  a  se- 
cretion does  not,  therefore,  indicate  its  antiseptic  value  in  that 
secretion,  for  when  it  does  not  liberate  formaldehyd  its  antiseptic 
effect  is  very  slight. 

Burnam  (1912)  tested  the  secretions  other  than  urine  in  cer- 
tain cases  of  Dr.  Howard  A.  Kelly.  The  following  are  his  results 
from  Hehner's  test,  which  reacts  very  delicately  to  both  hexa- 
methylenamine and  formaldehyd.  (The  urine  was  the  only 
secretion  that  was  positive  with  Burnam's  test,  which  reacts 
with  formaldehyd  in  amounts  above  i  :  150,000,  but  not  with 
hexamethylenamine.) 

1.  The  Bile. — In  10  cases  of  biliary  fistula,  60  grains  (4  gm.) 
a  day  gave  only  a  faint  test,  though  bile  containing  as  much  as 
i  :  50,000  gives  a  sharp  reaction. 

2.  The  Saliva. — Only  faint  traces. 

3.  Sputum. — In  three  cases  of  bronchitis,  absolutely  none  of 
the  drug  present. 

4.  Cerebrospinal  Fluid. — In  one  case  getting  15  grains  (i  gm.) 
every  three  hours  for  twenty-four  hours,  4  c.c.  of  the  spinal  fluid 
showed  mere  traces. 

In  all  these  fluids  the  drug,  either  hexamethylenamine  or 
formaldehyd,  was  not  present  in  amounts  above  i  :  150,000, 
and  therefore  was  absolutely  without  antiseptic  value.  Hanzlik 
(1910)  showed  that  there  was  no  formaldehyd  set  free  in  the 
saliva,  and  Fullerton  points  out  that  Sollmann's  demonstration 
of  the  time  required  for  the  development  of  formaldehyd  in 
alkaline  liquids  would  forbid  its  formation  in  any  free-running 
secretion.  It  is  to  be  noted  that  formaldehyd  in  the  urine  may 
lessen  the  heat  test  for  albumin  and  the  test  for  indican,  and  may 
give  Fehling's  reaction. 

Untoward  Effects. — In  acid  urine  it  sometimes  so  increases  the 
acidity  as  to  make  the  urine  irritating,  or  sets  free  enough  for- 
maldehyd to  do  this;  and  marked  vesical  pain,  frequent  burning 
micturition,  bloody  urine,  and  defoliation  of  the  bladder  mucous 
membrane  have  been  reported.  The  kidneys  are  also  irritated 
at  times,  though  Richardson  (1899)  showed  that  in  the  presence 
of  an  existing  nephritis  there  was  no  increase  in  albumin  or  casts. 
Coleman  (1903)  reported  the  following  untoward  sequelae:  irri- 
tation of  stomach,  diarrhea,  and  abdominal  pain;  irritation  of 
kidneys  and  bladder,  with  hematuria  and  hemoglobinuria ;  head- 

33 


514  PHARMACOLOGY  AND  THERAPEUTICS 

ache,  ringing  in  cars;  and  a  skin  rash  like  that  of  measles.  Crowe 
reports  that  of  95  cases  getting  an  average  dosage  of  75  grains 
(5  gm.)  a  day,  7  developed  painful  micturition  and  hematuria. 
He  has  noted  also  skin  rashes,  acute  catarrh  of  mucous  membranes, 
and  gastric  irritation.  Frothingham  (1909)  reported  that  very 
large  doses  could  be  given  to  guinea-pigs  without  toxicity,  though 
their  stomachs  were  prone  to  become  ulcerated  and  to  bleed.  He 
sometimes  got  necrosis  at  the  site  of  a  hypodermatic  injection  of 
the  drug.  Burnam  says  that  a  50  per  cent,  solution  is  not  irritant 
locally. 

Therapeutics  and  Administration. — From  the  above  it  is  seen 
that  there  is  no  question  of  the  frequent  value  of  hexamethylena- 
mine  as  a  disinfectant  in  the  urinary  tract.  For  this  purpose  it 
is  .given  in  amounts  of  5  to  20  grains  (0.3-1.3  gm.)  three  times  a 
day  with  large  quantities  of  water  to  favor  elimination  by  the 
kidneys.  If  the  urine  is  alkaline,  it  may  be  acidified  by  acid 
sodium  phosphate,  but  this  must  not  be  given  at  the  same  hour 
as  the  drug,  as  they  are  chemically  incompatible. 

As  proved  by  an  overwhelming  amount  of  experimental 
data,  outside  the  urinary  tract  hexamethylenamine  has  no 
therapeutic  value  whatever.  Even  in  the  urinary  tract  the  drug 
rarely  produces  enough  formaldehyd  to  render  the  urine  com- 
pletely destructive  to  bacteria. 

THERAPEUTIC    CLASSIFICATION    OF    DISINFECTANTS 

I.  GENERAL   DISINFECTANTS   AND   DEODORIZERS 

(a)  Used  in  dry  form — for  water-closets,  sinks,  and  cess-pools, 
copperas   (ferrous  sulphate),  naphthalin   (tar  balls),  lime,  and 
chlorinated  lime  are  preferred  because  cheap. 

(b)  Used  in  solution — for  utensils,  excreta,  bedding,  etc.,  from 
the  sick-room.     For  basins,  chambers,  bed-pans,  etc.,  a  solution 
of  mercuric  bichloride,  zinc  chloride,  or  phenol  is  employed.    The 
zinc  chloride  is  odorless,  an  obvious  advantage  over  carbolic, 
whose   universally   recognized    odor   suggests   unpleasant   sick- 
room experience.     In  full  strength,  Platt's  Chlorides,  a  proprie- 
tary, failed  to  kill  the  typhoid  bacillus  in  ten  minutes  (Hygienic 
Bulletin  Xo.  82).     The  bichloride  destroys  metallic  utensils. 

The  urine,  feces,  or  sputum  may  be  received  in,  and  mixed 
with,  a  3  per  cent,  solution  of  carbolic,  a  i  :  5000  solution  of 
mercuric  bichloride,  a  i  per  cent,  solution  of  zinc  chloride,  or 
one-quarter  its  bulk  of  quicklime.  The  mixture  should  be 
allowed  to  stand  for  half  an  hour. 

(c)  Used  as  gas—  for  rooms  and  contents,  bedding,  clothes, 
etc.,  formaldehyd,  sulphur  dioxide,  free  chlorine,  the  creosols  of 


DISINFECTANTS   FOR    SURGICAL   SUPPLIES  515 

smoke  (burning  sugar,  coffee,  brown  paper,  etc.).  It  is  difficult 
to  find  a  gaseous  disinfectant  that  will  penetrate  through  bed- 
clothes and  mattresses,  and  into  the  cracks  of  a  wall  or  floor. 

J.  S.  Billings  says  that  "terminal  disinfection  no  longer  holds 
a  prominent  place  in  the  control  of  infectious  diseases,  for  the 
reason  that  by  the  time  the  infective  agent  has  disappeared 
from  the  person  of  the  patient,  it  has  long  since  disappeared  from 
the  premises  and  surroundings." 

II.  PRESERVATIVES 

1.  Pharmaceutic — alcohol,  glycerin,  sugar,  benzoin,  aromatic 
oils,  boric  acid. 

2.  Foods — boric  acid,  borax,  saltpeter  (KNO3),  salicylic  acid, 
sodium  benzoate,  formaklehyd,  sodium  chloride  (butter,  ham, 
fish,  corned  beef),  smoke  (smoked  beef  and  ham),  sugar,  vinegar. 

3.  Anatomic    material — formaldehyd,    acetic    acid,    arsenic, 
alcohol,  glycerin,  potassium  bichromate. 

4.  Antitoxins,  vaccines — glycerin,  trichlorphenol,  phenol,  tri- 
kresol. 

Alcohol  is  the  most  useful  preservative  for  vegetable  drugs  in 
solution;  thus  tinctures  and  fluid  extracts  keep  well,  while  aqueous 
solutions,  such  as  infusions,  do  not.  A  saturated  solution  of  sugar 
is  antiseptic,  as  seen  in  jams  and  medicinal  syrups;  syrups  less 
than  saturated  will  ferment  or  mold.  Glycerin  is  a  much-used 
preservative  of  vegetable  extracts.  To  preserve  meat,  borax  and 
saltpeter  are  used,  or  the  meat  is  salted  or  smoked  (as  ham,  corned 
beef,  smoked  beef,  etc.) ;  through  exposure  to  smoke  it  absorbs  cre- 
osols  and  other  wood-tar  constituents.  Boric  acid,  sodium  benzo- 
ate, salicylic  acid,  and  formaldehyd  are  added  to  various  canned 
and  preserved  foods  and  to  milk,  cream,  and  butter.  Boric  acid 
will  also  retard  the  common  fungus  growth  in  solutions  of  chem- 
icals, such  as  cocaine.  A  too  much  used  preservative  of  milk  is 
formaldehyd,  which,  in  amounts  sufficient  to  keep  milk  for  a  week, 
cannot  be  detected  by  its  odor.  Lard  may  be  kept  from  becoming 
rancid  for  a  time  by  the  presence  of  benzoin,  as  in  benzoinated 
lard.  Butter  is  believed  to  keep  better  when  it  is  salted.  Chem- 
ically preserved  foods  (embalmed  foods)  are  usually  less  readily 
digested  than  normally,  as  their  tissues  are  hardened,  and  also 
the  preservatives  interfere  with  the  activity  of  the  digestive 
ferments. 

III.  DISINFECTANTS   FOR    SURGICAL    SUPPLIES 

For  utensils,  surgical  instruments,  and  dressings  the  best  of  all 
disinfectants  is  live,  superheated  steam  at  220°  to  225°  F.  The 


516  PHARMACOLOGY  AND  THERAPEUTICS 

next  best  is  dry  heat.  Instruments  can  be  boiled  with  water,  or 
placed  in  5  per  cent,  phenol  or  70  per  cent,  alcohol,  or  a  mixture 
of  phenol  and  alcohol.  Catgut  is  sterilized  by  boiling  with  cumol 
at  330°  F.  (165°  C.).  Dressings,  absorbent  cotton,  etc.,  may  be 
sterilized  by  dry  heat  or  formaldehyd. 


IV.  DISINFECTANTS  FOR  LOCAL   USE  ABOUT  THE   BODY 

1.  Skin. — (a)  For  the  patient's  skin,  preliminary  to  operation. 
— Scrubbing  with  soft  soap  and  application  of  tincture  of  iodine. 

(b)  For  the  surgeon's  hands. — Chlorine,  generated  by  rubbing 
the  hands  with  chlorinated  lime  and  washing  soda;  potassium 
permanganate,  i  :  5000,  followed  by  oxalic  acid  to  remove  the 
brown  stains;  tincture  of  iodine;  alcohol;  3  per  cent,  phenol;  and 
mercuric  bichloride  i  :  2000.     It  is  of  no  use  to  dash  the  hands  into 
an  antiseptic  solution,  then  think  them  disinfected.     The  bichlo- 
ride of  mercury,  for  example,  requires  many  minutes  for  its 
action. 

(c)  For  the  obstetrician's  hands. — A  half  per  cent,  solution 
of  lysol  or  of  the  official  compound  solution  of  cresol.     Both  are 
rather  soapy  and  serve  as  lubricants  in  vaginal  examinations. 
Their  slipperiness  interferes  somewhat  in  the  handling  of  instru- 
ments. 

All  antiseptics  for  the  hands  and  skin  are  preceded  by  thorough 
scrubbing  with  green  soap  and  hot  water.  This  acts  by  removing 
the  loose  epithelium  and  bacteria,  and  is  probably  of  quite  as 
much  value  as  most  of  the  antiseptics  in  freeing  the  skin  from 
germ  life.  In  open  wounds  there  are  very  few  antiseptics  that  do 
not  harm  the  tissues  of  the  host  more  than  they  do  those  of  the 
bacteria. 

(d)  In  skin  diseases. — The    organic    substances,  tar,  oil   of 
cade,  naphthalin,  balsam  of  Peru,  benzoin,  resorcinol,  salicylic 
acid,  pyrogallol,  ichthyol,  formaldehyd;  and  the  inorganic  sub- 
stances, mercuric  chloride,  ammoniated  mercury,  mercurial  oint- 
ment, boric  acid,  sulphur,  iodine  and  its  compounds. 

2.  In  eye — boric  acid,  silver  salts,  copper  sulphate,  mercuric 
oxide  ointment. 

3.  In  nose — camphor,  menthol,  oil  of  eucalyptus,  boric  acid, 
the  silver  salts,  peroxide  of  hydrogen. 

4.  In  mouth  and  throat — boric  acid,  the  silver  salts,  hydrogen 
dioxide,  mercuric  chloride,  ferric  chloride,  glycerin,  iodine. 

5.  In  urethra  and  bladder — the  silver  salts,  potassium  per- 
manganate, zinc  sulphate. 

6.  In  vagina — compound   solution  of  cresol,   creolin,   lysol, 
phenol,  ichthyol,  mercuric  chloride,  boroglycerin. 


THE   HEAVY   METALS  517 

7.  In  rectum — boric  acid,  silver  salts,  quinine  bisulphate,  cal- 
cium permanganate. 

8.  In  larynx  and  bronchi  by  inhalation — oil  of  eucalyptus, 
camphor,  menthol,  creosote,  benzoin. 

9.  In  open  wounds — iodoform  and  the  phenol  iodine  com- 
pounds,  mercuric   chloride,   phenol,   potassium   permanganate, 
balsam  of  Peru  (gauze),  ichthyol,  aluminium  acetate,  bismuth 
subiodide,  zinc  sulphate  (in  red  wash),  boric  and  salicylic  acids 
(Thiersch's  solution),  hydrogen  dioxide.     As  a  temporary  ap- 
plication to  war  wounds,  Keilty  and  Packer  recommend  an  oint- 
ment made  of  70  per  cent,  of  castor  oil  with  wax  and  spermaceti, 
and  the  addition  of  10  per  cent,  of  thymol  and  tricresol. 

V.  DISINFECTANTS   TO   BE    GIVEN   BY   MOUTH 

For  the  stomach — sodium  salicylate,  10  grains  (0.7  gm.);  resor- 
cinol,  10  grains  (0.7  gm.);  sodium  sulphocarbolate,  10  grains 
(0.7  gm.);  creosote,  5  minims  (0.3  c.c.);  aromatic  oils,  5  minims 
(0.3  c.c.). 

For  the  intestines — acetyl-salicylic  acid,  salol,  naphthalin, 
beta-naphthol,  trimethol,  or  ichthyol,  in  dose  of  5  grains  (0.3 
gm.)  several  times  a  day. 

After  absorption — to  have  a  remote  local  effect  in  their  excre- 
tion. 

(a)  Urinary  tract — certain  of  the  volatile  oil  series  (turpentine, 
balsam  of  copaiba,  oil  of  sandalwood,  cubebs,  buchu,  uva-ursi), 
hexamethylenamine  (urotropin),  benzoates,  salol. 

(b)  Respiratory  tract — volatile  oil  series   (turpentine,  terpin 
hydrate,  cubebs,  tar,  creosote). 

(c)  In  other  secretions  or  body  fluids — no  known  drug.    Hexa- 
methylenamine, formerly  employed,  has  been  proven  worthless. 

THE   HEAVY   METALS 

The  heavy  metals,  though  differing  markedly  in  some  of  their 
details  of  action  and  in  their  therapeutic  uses,  have  certain  phar- 
macologic  actions  in  common.  Their  salts  tend  to  precipitate 
proteins,  forming  metallic  albuminates  of  variable  composition. 
The  salts  which  are  most  readily  dissociable  into  ions  act  most 
rapidly  and  tend  to  be  irritant.  They  may  even  be  caustic,  caus- 
ing death  of  tissue.  The  soluble  salts,  through  precipitation  of 
the  proteins  of  the  cells,  tend  to  be  astringent.  The  organic  prep- 
arations and  double  salts  tend  to  dissociate  less  easily  and  have 
less  local  action.  The  salts  of  inorganic  acids  tend  to  be  especially 
astringent  from  the  setting  free  of  the  acid. 

The  absorption  of  most  of  the  salts  is  slow,  and  their  excretion 


518  PHARMACOLOGY   AND   THERAPEUTICS 

also  very  slow,  and  chronic  poisoning  by  some  of  the  metals  may 
follow  the  repeated  ingestion  for  many  days  of  very  minute 
quantities.  They  are  mostly  excreted  by  the  kidneys  and  the 
gastro-intestinal  tract;  and  in  the  poisoning  these  organs  tend  to 
be  inflamed. 

The  nervous  system  is  also  sensitive  to  the  metals,  peripheral 
neuritis,  excitability,  and  scleroses  in  the  brain  or  cord  being 
sometimes  manifestations  of  metallic  poisoning. 

MERCURY 

There  are  many  official  salts  and  preparations  of  mercury 
(hydrargyrum),  and  their  actions  and  uses  are  so  distinct  that 
they  may  well  be  considered  separately  according  to  their  ther- 
apeutic uses.  The  therapeutic  classes  are:  (i)  The  disinfectants. 
(2)  The  antisyphilitics.  (3)  The  cathartics.  (4)  Those  with 
special  uses. 

I.     The  Disinfectants 

(a)  Mercuric  chloride,  hydrargyri  chloridum  corrosivum,  HgClo, 
known  also  as  bichloride  of  mercury  or  corrosive  sublimate, 
is  soluble  in  13  parts  of  water  and  3  of  alcohol.  The  U.  S. 
Pharmacopoeia  has  introduced  a  bichloride  tablet,  Toxitabella 
hydrargyri  chloridi  corrosivi,  which  contains  mercuric  chloride 
about  7^  grains  (0.45-0.55  gm.)  and  an  equal  amount  of  sodium 
chloride.  It  must  be  of  angular  shape  (not  discoid),  must  bear 
the  word  "poison"  and  skull  and  cross-bones,  and  must  be  colored 
blue,  preferably  with  sodium  indigotindisulphonate. 

The  solution  in  water  takes  place  slowly,  but  is  hastened  by 
the  addition  of  some  sodium  or  ammonium  chloride.  These 
chlorides,  however,  prevent  the  ready  dissociation  of  the  bichlo- 
ride into  ions,  and  reduce  the  antiseptic  power  about  half 
(Wolf).  In  Paul  and  Krony's  experiments  the  number  of  an- 
thrax colonies  obtained  after  six  minutes'  exposure  of  the  spores  to 
bichloride,  i  :  60,  was  8,  while  when  the  bichloride  was  mixed  with 
an  equal  amount  of  sodium  chloride,  they  obtained  32  colonies, 
and  with  four  times  as  much  sodium  chloride,  382  colonies. 
These  chlorides  retard  correspondingly  the  precipitation  of  al- 
bumin. Mercuric  chloride  has  many  incompatibles,  such  as 
alkaloids,  alkalies,  lime-water,  and  soap.  A  large  basin  of  bi- 
chloride antiseptic  solution  will  be  destroyed  by  a  very  small 
amount  of  green  soap.  It  is  also  decomposed  by  carbonates, 
silicates,  and  sulphates,  such  as  occur  in  the  natural  waters; 
so  that  in  making  its  solutions,  distilled  water  is  preferable. 

A  solution  of  i  :  1,000,000  will  kill  protozoa,  a  solution  of 
i  :  10.000  will  prevent  the  growth  of  molds  and  bacteria.  It 


ig.  64. — Destruction  of  tubular  epithelium  caused  by  poisoning  with  mercury 
bichloride  (MacCallurn) . 


THE    ANTISYPHILITICS  519 

takes  some  time  for  their  destruction,  however,  and  it  is  absurd  to 
suppose  an  instrument  or  the  hands  to  be  sterilized  by  a  moment- 
ary dipping  or  rinsing  of  them  in  the  solution.  The  spores  of 
bacteria  are  much  more  resistant  than  the  germs  themselves. 
The  bichloride  acts  by  forming  a  chemical  precipitate  with  the 
proteins  of  the  protoplasm;  as  a  consequence,  it  has  little  penetrat- 
ing power  and  is  quickly  rendered  practically  useless  by  albumin- 
ous fluids.  It  may  coagulate  an  albuminous  envelope  about 
bacteria  without  killing  them. 

Locally,  its  solutions  are  astringent  and  irritating,  and,  if 
strong,  are  corrosive  to  the  tissues.  Even  very  weak  solutions,  if 
much  used,  cause  roughening  and  discoloration  of  the  skin,  and 
in  the  form  of  a  continuous  wet  dressing  may  produce  a  derma- 
titis or  a  pustular  rash. 

In  i  :  4000  to  i  :  1000  aqueous  solution  mercuric  chloride  has 
been  one  of  the  most  used  antiseptics  for  the  hands  of  the  surgeon 
or  obstetrician,  for  the  skin  preliminary  to  operation,  for  infected 
wounds,  for  excreta,  and  in  i  :  10,000  solution  as  an  irrigation  in 
any  accessible  body  cavity,  as  throat,  vagina,  uterus,  bladder,  etc. 
It  is  also  used  in  fungus  and  bacterial  skin  diseases  and  for  pubic 
lice. 

Harrington's  solution,  as  used  at  the  Mayo  Clinic,  is  mercuric 
chloride,  0.8  gm.;  hydrochloric  acid,  60  gm.;  distilled  water, 
300  gm.;  alcohol,  640  gm.;  i.  e.,  i  :  1250  by  weight. 

(6)  The  other  mercurial  antiseptics  are  less  employed.  The 
ointment  of  mercury  in  two  strengths,  viz.,  mercurial  ointment 
(unguentum  hydrargyri),  50  per  cent.,  and  blue  ointment  (un- 
gu  en  turn  hydrargyri  dilutum),  33  per  cent.,  and  the  ointment  of 
ammoniated  mercury  (white  precipitate  ointment)  are  employed 
in  fungous  and  bacterial  skin  diseases ;  the  ointment  of  the  nitrate 
of  mercury  (citrine  ointment)  is  used  expecially  for  ring-worm. 
The  ointment  of  the  yellow  oxide  is  preferred  about  the  eye,  as  in 
blepharitis,  conjunctivitis,  and  keratitis. 

Schamberg,  Kolmer,  and  Raiziss  (1917)  have  brought  for- 
ward mercurophen  (sodium  oxymercury  orthonitrophenolate) 
as  a  salt  which,  against  Staphylococcus  aureus,  has  in  aqueous 
solution  50  times  the  disinfectant  power  of  bichloride,  and  in 
ascitic  fluid  200  times  the  power  of  bichloride. 

II.    The  Antisyphilitics 

As  local  applications  to  venereal  sores,  mercuric  chloride, 
calomel,  and  the  ointments  of  mercury  and  ammoniated  mercury 
are  employed.  Mercurial  ointment  (unguentum  hydrargyri) 
contains  50  per  cent.,  and  the  diluted  mercurial  ointment  (un- 


520  PHARMACOLOGY   AND   THERAPEUTICS 

guentum  hydrargyri  dilutum),  30  per  cent,  of  mercury.  Black 
wash  (lotio  nigra,  N.  F.)  is  calomel,  4  grains  (0.25  gm.),  to  lime- 
water,  i  ounce  (30  c.c.);  yellow  wash  (lotio  flava,  N.  F.)  is  bichlo- 
ride, 1 1  grain  (0.09  gm.),  to  lime-water,  i  ounce  (30  c.c.). 

For  the  systemic  action  mercury  is  administered  by  inunction, 
by  mouth,  and  by  hypodermatic  or  intravenous  injection.  For 
inunction  the  mercurial  ointment  is  regularly  employed,  but  it  is 
dirty  and  tends  to  irritate  the  skin,  and  its  absorption  is  uncertain. 
Ten  to  30  grains  are  rubbed  well  into  the  softer  parts  of  the  skin 
every  day  or  two,  a  new  area  being  chosen  for  each  successive 
inunction,  on  account  of  irritation.  The  favorite  sites  are  the 
inner  surfaces  of  the  thighs  and  arms,  and  the  chest,  back,  and 
abdomen.  Oleate  of  mercury  and  white  precipitate  ointment  are 
occasionally  used  instead  of  mercurial  ointment.  Weil  and 
Elliott  have  shown  that  the  mercury,  ammoniated  mercury 
(white  precipitate),  and  calomel  ointments  will  mercurialize 
a  patient  more  readily  than  an  ointment  made  from  the  non- 
volatile salts  such  as  the  salicylate  and  the  oxides. 

By  mouth,  the  favorites  are  the  biniodide,  T^  grain  (0.004  gm.), 
and  the  protoiodide,  \  grain  (0.015  g111-),  and  for  children  the 
mercury  with  chalk,  i  grain  (0.06  gm.).  The  bichloride,  dose,  -£% 
grain  (0.002  gm,),  is  sometimes  given  in  a  mixture  with  potassium 
iodide,  with  which,  however,  it  changes  to  the  biniodide. 

For  deep  intramuscular  injection  the  insoluble  mercuric 
salicylate  and  the  soluble  bichloride,  biniodide,  and  benzoate  are  the 
favorites.  The  former  is  insoluble  in  water  or  oil,  and  is  used  in 
10  to  30  per  cent,  admixture  with  liquid  paraffin  or  olive  oil. 
According  to  Lascoff,  it  makes  the  best  mixture  if  half  per  cent, 
of  lanolin  is  added.  The  dose  is  \  to  \\  grains  (0.03-0.1  gm.), 
injected  into  the  buttock  once  a  week,  or  every  five  days,  or  in 
urgent  cases  every  second  day.  More  or  less  soreness,  as  of  a 
bruise,  may  follow  the  injection  for  a  day  or  two,  and  occasionally 
headache,  languor,  nausea,  and  diarrhea.  The  benzoate,  dose 
i  grain  (0.06  gm.),  and  the  bichloride  and  biniodide,  dose  y1^ 
to  i  grain  (0.006-0.012  gm.),  are  more  readily  absorbed,  so  must 
be  administered  every  second  day.  The  bichloride  is  irritating, 
and  also  destroys  the  needles.  The  advantages  of  the  hypoder- 
matic method  are :  the  exact  dosage,  the  cleanliness,  and  the  close 
supervision  of  the  patient  which  are  gained  by  the  necessarily 
frequent  visits. 

In  comparing  mercury  with  salvarsan,  Schamberg  and  Kolmer 
found  that  in  the  test-tube  salvarsan  was  more  destructive  to 
animal  parasites  and  mercury  more  destructive  to  vegetable 
organisms. 

The  intravenous  route  is  not  much  employed  because  of  the 


THE    CATHARTICS  521 

danger  of  thrombosis  or  phlebitis.  The  dose  recommended  is 
£  grain  (o.oi  gm.)  of  the  bichloride  in  2\  drams  (10  c.c.)  of  distilled 
water,  or  \  to  i^  grains  (0.03-0.1  gm.)  of  the  benzoate  in  i  per 
cent,  normal  saline.  To  avoid  thrombosis  Nixon  mixes  the 
10  c.c.  of  bichloride  solution  with  10  c.c.  of  blood  drawn  into  the 
syringe,  and  injects  the  mixture.  Mercurialized  human  or  horse 
serum  is  also  employed,  ^  or  ^  grain  (0.0012-0.0024  gm.)  of 
the  bichloride  being  added  to  about  i  ounce  (30  c.c.)  of  serum. 

For  cerebrospinal  syphilis,  tabes,  paresis,  etc.,  the  intraspinal 
injection  of  mercurialized  human  or  horse  serum  may  be  employed 
in  amounts  representing  -^  grain  (0.0012  gm.)  of  mercuric 
bichloride.  It  may  give  the  same  sequelae  as  intraspinal  salvar- 
sanized  serum  (see  Salvarsan). 

III.    The  Cathartics.     (See  under  Cathartics.) 

IV.    Those  with  Special  Uses,  Other  Than  Those  Mentioned 

Mercury  subsulphate  (turpeth  mineral),  as  an  emetic  in  croup. 
Dose,  2  grains  (0.13  gm.)  for  a  child  of  six. 

Calomel,  in  croupous  laryngitis;  5  to  20  grains  volatilized  on 
a  tin  plate  or  in  a  teaspoon,  and  inhaled — not  often  employed  at 
the  present  time.  Calomel  may  be  of  value  at  the  beginning  of 
a  course  of  diuresis.  If  ^  is  absorbed,  it  tends  to  irritate  kidney 
cells,  but,  as  a  matter  of  fact,  most  of  it  fails  of  absorption 
and  passes  out  by  the  rectum.  It  is  probable  that  much  of  the 
value  of  calomel  in  inducing  diuresis  is  due  to  the  relief  of  the 
splanchnic  circulation  through  purging. 

In  malaria,  Barlow  uses  bichloride  intravenously,  the  dose 
being  |  grain  (0.015  Sm-)  m  t  ounce  (20  c.c.)  of  saline  solution. 
He  claims  it  to  be  especially  useful  as  an  adjunct  to  quinine,  in 
the  refractory  cases. 

The  use  of  mercury  succinimide,  ^  grain  (0.0012  gm.)  every 
second  clay  for  30  injections,  has  been  recommended  in  tuber- 
culosis, but  has  not  proved  curative. 

Systemic  Action  of  Mercury  Salts. — After  absorption  mercury 
becomes  generally  distributed  throughout  the  body,  but  is  espe- 
cially stored  up  in  the  liver.  In  its  therapeutic  use  it  has  .little 
direct  action  on  any  of  the  tissues ;  but  an  improvement  in  the  blood 
and  nutritional  state  is  believed  to  follow  repeated  small  doses. 

Elimination. — It  is  eliminated  by  the  salivary  glands,  stomach, 
liver,  kidneys,  skin,  colon,  and  rectum.  It  appears  in  the  urine 
in  three  to  twenty-four  hours  after  ingestion,  and  in  the  feces 
after  twenty-four  hours  (Lambert  and  Patterson).  After  sub- 
cutaneous injections  for  syphilis,  Mironowitsch  found  more 
mercury  in  the  sweat  than  in  the  urine.  The  major  portion 


522  PHARMACOLOGY   AND   THERAPEUTICS 

passes  through  the  walls  of  the  colon  and  upper  rectum  and 
may  cause  considerable  irritation  or  actual  colitis.  Koldewijn 
applied  mercurial  ointment  to  cows,  and  was  unable  to  find 
mercury  in  the  milk;  but  Haas  found  that  -£%  grain  (0.0005  g111-) 
of  mercuric  chloride  given  three  times  a  day  to  the  mothers  of 
syphilitic  infants  had  a  slight  but  positive  remedial  effect  on  the 
nursing  child.  It  is  said  that  mercury  has  been  detected  in 
the  tissues  six  months  after  its  administration  has  been  stopped. 

Kidneys. — Even  after  cathartic  doses  of  a  mercurial  the  metal 
has  been  found  in  the  urine.  Mercuric  chloride  has  a  special  de- 
structive action  upon  the  epithelium  of  the  convoluted  tubules,  and 
has  been  employed  to  produce  experimental  tubular  nephritis.  In 
acute  poisoning  there  may  be  a  violent  exudative  nephritis  or  ne- 
phrosis;  in  subacute  or  chronic  poisoning  there  may  be  a  diffuse 
nephritis,  the  destructive  effects  in  the  tubules  being  followed  by 
changes  in  the  glomeruli  and  increase  of  connective  tissue.  Foster 
reports  a  case  of  bichloride  poisoning  that  died  after  forty-one 
days  with  the  kidney  lesion  almost  strictly  confined  to  the  tubu- 
lar epithelium.  The  non-protein  nitrogen  rose  to  238  mg.  per 
100  c.c.  of  blood,  but  there  was  no  chloride  or  water  retention. 
Calomel  is  frequently  employed  to  aid  other  diuretics;  but  it 
probably  acts  by  catharsis  to  relieve  the  kidneys,  rather  than  by 
direct  irritation  of  the  kidney  cells. 

Toxicology  of  Mercury. — i.  The  mildest  form  of  poisoning 
has  for  its  prominent  feature  "mercurial  stomatitis,"  or,  as  it  is 
commonly  called,  "salivation."  This  is  a  not  uncommon  result 
of  mercury  salts  administered  as  remedies,  even  a  grain  or  two  of 
calomel  being  sufficient  in  some  cases  to  produce  it.  It  is  much 
more  readily  produced  in  nephritis  than  when  the  kidneys  are 
unimpaired.  In  several  instances  the  author  has  seen  salivation 
in  nephritis  from  two  or  three  compound  cathartic  pills  (each  of 
which  contains  one  grain  of  calomel). 

The  symptoms  of  "salivation"  are:  profuse  flow  of  saliva, 
metallic  taste,  very  foul  breath,  coated  swollen  tongue,  soreness 
or  ulceration  of  the  gums  or  inside  of  the  mouth,  soreness  of  the 
tooth-sockets  (test  patient  by  having  him  hit  teeth  together) ,  and 
loosening  of  the  teeth.  The  profuse  salivation  may  go  on  to 
inflammation  of  the  salivary  glands  and  necrosis  of  parts  of  the 
mouth  and  jaw.  In  addition,  the  patient  feels  ill  and  there  may  be 
headache,  lassitude,  muscular  weakness,  and  diarrhea;  occasion- 
ally there  is  constipation.  As  a  prophylactic  during  the  adminis- 
tration of  mercury  salts,  and  as  treatment  for  mercurial  stomatitis, 
a  mouth-wash  of  a  saturated  solution  of  potassium  chlorate 
with  a  little  tincture  of  myrrh  is  recommended. 

2.  Severe  acute  poisoning  is  usually  due  to  the  bichloride, 


THE    CATHARTICS  523 

either  from  swallowing  the  tablets  or  a  solution  (often  with 
suicidal  intent) ,  or  from  the  retention  of  strong  solutions  used  as 
uterine  or  vaginal  douches.  From  mouth  doses  the  dominant 
lesion  is  nephritis;  from  vaginal  douches  it  is  generally  colitis. 
Taken  by  mouth,  bichloride  gives  a  strongly  metallic  and  astrin- 
gent taste.  If  the  swallowed  liquid  is  strong  encugh  there  is  local 
corrosion  of  mouth,  esophagus,  and  stomach,  followed  by  ab- 
dominal pain  and  vomiting.  There  may  be  copious  serous  or 
bloody  stools,  albuminous  or  bloody  urine,  or  suppression  of  the 
urine,  delirium,  coma,  collapse  and  death,  or  slow  recovery. 
Postmortem  examination  shows  the  local  corrosion  of  the  upper 
part  of  the  alimentary  tract,  and  also  acute  colitis,  acute  proctitis, 
and  acute  nephritis.  In  the  enterocolitis  there  may  be  extensive 
necrosis;  in  the  nephritis  there  are  fatty  degeneration  and  necrosis 
of  the  cells  of  the  convoluted  tubules.  Pericarditis  is  reported. 
There  is  occasionally  a  period  of  a  day  or  two  before  the  onset  of 
the  symptoms.  In  a  patient  that  died  ten  days  after  taking 
225  grains  (15  gm.),  Rosenbloom  found  most  of  the  mercury  in 
the  liver,  but  much  also  in  the  large  and  small  intestines,  heart, 
kidneys,  blood  and  muscles,  and  in  the  stomach  and  intestinal 
contents. 

If  the  patient  does  not  die  quickly,  he  may  be  ill  for  days  or 
weeks,  with  marked  salivation,  inflammatory  and  gangrenous 
lesions  of  the  pharynx,  cheeks,  and  hard  palate,  spongy  and 
broken-down  gums,  loss  of  the  teeth,  gastritis,  colitis,  and  nephri- 
tis. He  may  eventually  recover,  or  may  die  of  uremia  or  colitis 
or  general  prostration.  Arterial  pressure  may  be  high  until  col- 
lapse sets  in.  The  leucocytes  are  regularly  high  (Vogel).  Lewis 
and  Rivers  report  acidosis. 

Treatment. — Recovery  has  taken  place  after  nine  days  of 
anuria,  a  fact  which  indicates  the  value  of  vigorous  and  persistent 
treatme'nt. 

At  the  outset,  after  bichloride  is  swallowed,  white  of  egg  or 
milk  should  be  given  to  form  non-corrosive  albuminates;  and 
these  should  promptly  be  removed  from  the  stomach  by  lavage  or 
vomiting  to  prevent  absorption.  Bland  oils  and  other  demulcents 
may  then  be  given  to  soothe  damaged  membranes.  The  sys- 
temic treatment  is  eliminant.  As  the  mouth,  colon,  and  kidney 
symptoms  develop,  these  require  vigorous  treatment.  Potassium 
chlorate  and  myrrh  make  a  favorite  mouth-wash,  and  if  the  mouth 
is  foul,  peroxide  of  hydrogen. 

The  Lambert- Patter  son  Treatment. — Perhaps  the  most  highly 
successful  form  of  treatment  is  that  of  S.  W.  Lambert  and  H.  S. 
Patterson,  of  St.  Luke's  Hospital,  New  York.  They  advise 
immediate  administration  of  the  whites  of  several  eggs,  followed 


524  PHARMACOLOGY   AND   THERAPEUTICS 

by  lavage.  On  admission  to  the  hospital  they  give  another 
thorough  lavage  and  introduce  through  the  tube  a  pint  of  milk, 
following  this  in  one  hour  by  another  lavage  if  the  nausea  and 
vomiting  continue.  As  soon  as  the  stomach  permits  they  begin 
the  following  routine:  (i)  Hourly  liquid  by  mouth,  8  ounces 
(240  c.c.)  of  milk  alternating  with  8  ounces  (240  c.c.)  of  a  mixture 
of  potassium  bitartrate  and  sugar,  each  i  dram  (4  gm.),  lactose 
4  drams  (15  gm.),  lemon  juice,  one  ounce  (30  c.c.),  with  boiling 
water,  i  pint  (480  c.c.).  (2)  A  continuous  rectal  drip  of  a 
solution  of  potassium  acetate,  3j  (4  gm.)  to  Oj  (480  c.c.).  (3) 
Lavage  of  the  stomach  twice  daily.  (4)  Irrigation  of  the  colon 
twice  daily.  (5)  A  daily  hot-pack  sweat.  The  treatment  is 
continued  until  there  is  no  mercury  in  the  urine  on  two  successive 
days.  In  some  of  the  cases  received  late  this  stage  has  not  been 
reached  for  as  much  as  three  weeks.  In  a  number  of  cases  treated 
by  this  type  of  alkali-water  therapy,  even  after  anuria  for 
several  days  the  urine  had  returned  to  normal  in  three  or  four 
weeks,  and  the  kidneys  were  apparently  permanently  restored. 

Macnider  has  shown  that  alkalies  seemed  to  give  the  best  pro- 
tection against  the  development  of  tubular  nephritis  in  experi- 
mental uranium  poisoning.  A  case  reported  by  H.  C.  Wood 
illustrates  a  possible  danger  from  copious  water  ingestion  if 
the  anuria  is  not  overcome.  The  patient  passed  only  3!  ounces 
of  urine  in  seven  days  and  on  the  four  subsequent  days  4,  9,  n, 
and  14  ounces,  and  on  the  twelfth  day  died  of  pulmonary  edema. 

Biirmeister  recommends  the  substitution  of  new  blood  for 
the  mercury-containing  blood  by  repeated  copious  venesections 
and  transfusions.  Wilms  uses  calcium  sulphide  intravenously, 
i  grain  (0.06  gm.)  in  i  ounce  (30  c.c.)  of  tap-water  filtered  hot  for 
each  grain  of  mercury  salt  ingested.  He  also  gives  i  grain 
(0.06  gm.)  every  hour  by  mouth.  Sodium  phosphite  has  been 
proposed,  but  it  has  a  reducing  value  only  in  the  stomach. 
Hall's  antidote,  consisting  of  potassium  iodide,  quinine  hydro- 
chloride  and  water,  has  been  shown  by  Barbour  to  be  valueless. 
Decapsulation  of  the  kidneys  has  overcome  the  anuria  in  some 
cases. 

3.  Chronic  Poisoning. — This  is  seen  among  makers  of  mirrors, 
barometers,  thermometers,  and  felt  for  felt  hats,  the  hides  being 
impregnated  with  mercury.  It  also  occasionally  results  from  the 
mercury  treatment  of  syphilis.  The  writer  saw  a  case  in  a  man 
who  had  used  cinnabar  (mercuric  sulphide)  in  an  Indian  make-up. 
Besides  the  salivation,  the  poisoning  shows  the  usual  effects  of 
the  heavy  metals  on  the  nutrition,  the  alimentary  tract,  the  ner- 
vous system,  and  the  blood.  These  effects  are:  loss  of  appetite, 
nausea,  and  other  derangements  of  digestion,  constipation  or 


LEAD  525 

diarrhea,  colic,  anemia,  loss  of  flesh  and  strength,  and  aching  in 
bones  and  joints.  There  may  be  a  general  cachexia.  There  is  no 
line  on  the  gums,  as  in  lead-poisoning.  The  effect  on  the  nervous 
system  may  be  pronounced.  There  are:  a  tremor  of  the  hands 
and  lips  or  the  whole  body,  irritability  of  temper,  fear,  hallucina- 
tions, loss  of  memory,  mental  weakness,  loss  of  will-power,  and 
perhaps  a  peripheral  neuritis  (Starr  says  rare,  if  occurs  at  all). 
The  diagnosis  is  confirmed  by  finding  mercury  in  the  urine  or 
feces. 

The  treatment  is  removal  of  the  patient  from  exposure  to  the 
mercury,  potassium  iodide  and  free  water-alkali  therapy  to 
promote  elimination,  and  care  for  the  nervous  condition,  the  mal- 
nutrition, the  anemia,  and  the  salivation.  Oliver  thinks  iodide 
is  useless. 

During  the  treatment  of  syphilis  a  sore  throat  or  mouth 
due  to  mercury  may  sometimes  be  attributed  to  the  disease,  and 
may  persist  until  the  mercury  is  stopped.  Busch  says  that  mer- 
cury is  contraindicated  in  Addison's  disease. 

LEAD 

The  lead  (plumbum)  salts  are  not  much  employed  in  medicine. 

Preparations. — (a)  For  External  Use. — The  acetate  and  sub- 
acetate  are  antiseptic  and  astringent  and  are  soothing  to  wounds 
and  bruises.  Liquor  plumbi  subacetatis  (Goulard's  extract)  con- 
tains about  25  per  cent,  of  lead  subacetate.  Liquor  plumbi 
subacetatis  dilutus  (lead-water)  is  a  4  per  cent,  solution  of  the 
liquor.  It  is  used  as  a  wet  dressing  for  wounds  and  bruises,  and 
as  a  soothing  application  in  skin  diseases,  sunburn,  ivy  poison, 
and  eczema. 

Lead  and  opium  wash  (Lotio  Plumbi  et  Opii,  N.  F.)  contains 
lead  acetate,  26  grains  (1.75  gm.),  tincture  of  opium,  52  minims 
(3.5  c.c.),  and  water  to  make  3^  ounces  (100  c.c.). 

Lead  oleate  is  a  sticky,  insoluble  mass,  which  is  used  as  the 
mechanical  basis  of  plasters.  It  is  known  as  "lead  plaster." 
From  the  prolonged  application  of  plasters  it  has  caused  poison- 
ing. 

Lead  sulphate  is  present  as  a  sediment  in  liquor  alumini  aceta- 
tis  (Burow's  solution) ,  when  this  is  made  of  lead  acetate  and  alum. 
It  should  be  filtered  off,  as  it  has  caused  poisoning. 

(b)  For  internal  use  the  only  salt  employed  is  the  acetate, 
dose,  2  grains  (0.13  gm.).  Its  only  use  is  to  overcome  intractable 
diarrhea,  as  from  tuberculous  enteritis  or  colitis,  and  to  induce  a 
temporary  obstipation,  as  in  operations  about  the  anus  or  rectum. 
Pills  of  lead  and  opium,  N .  F.,  contain  i  grain  (0.06  gm.)  each 
of  lead  acetate  and  powdered  opium. 


526  PHARMACOLOGY   AND   THERAPEUTICS 

Toxicology. — Though  lead  has  but  little  use  in  therapeutics, 
it  is  of  importance  to  physicians  because  of  the  frequency  of 
chronic  lead -poisoning  or  plumbism.  This  occurs  very  commonly 
among  painters  and  plumbers  and  other  workers  in  lead  (type, 
lead  pipe,  shot,  pottery  glazing,  enamelware,  etc.),  and  is  one  of 
the  diseases  often  met  with  in  clinics  and  hospitals.  It  may  even 
result  from  hair-washes  containing  lead  acetate,  from  water  that 
has  stood  in  lead  pipes,  from  canned  food  with  lead  in  the  solder 
of  the  cans,  from  wall-paper,  or  from  the  prolonged  application 
of  plasters  (with  lead  plaster  base)  to  the  skin.  Gottheil  reports 
a  case  of  death  from  the  sediment  (lead  sulphate)  in  Burow's 
solution  made  with  lead  acetate  and  alum.  Stewart  reports 
64  cases  in  children  from  eating  buns  colored  with  chrome 
yellow. 

The  symptoms  are:  Anemia  and  wasting,  foul  breath,  bad 
taste  in  the  mouth,  loss  of  appetite,  especially  in  the  morning, 
gastric  and  intestinal  disturbances,  pains  in  the  joints  and  bones, 
and  spots  before  the  eyes.  Sailer  and  Speese  found  almost  com- 
plete absence  of  gastric  juice  in  10  out  of  12  subjects.  Chronic 
nephritis  is  very  common,  and  the  arterial  pressure  tends  to  be 
high.  Blackfan  gives  the  symptoms  in  children  as  change  in  dis- 
position, peevishness,  restlessness  at  night,  appetite  poor,  breath 
foul,  hemorrhage  from  gums,  pain  in  epigastrium,  constipation, 
and  pain  in  legs.  In  children  the  paralysis  usually  affects 
the  legs  rather  than  the  arms.  Sixteen  of  Stewart's  64  cases 
had  convulsions.  In  rabbits,  Charteris  found  that  lead  car- 
bonate produced  a  marked  anemia,  with  degeneration  of  both 
the  leukoblastic  and  the  erythroblastic  elements  of  the  bone- 
marrow. 

In  addition  to  these  symptoms  there  are  usually  certain  mani- 
festations which  are  characteristic  of  lead,  and  determine  the  type 
of  the  complaint  to  the  physician,  viz. : 

i.  Colic. — Lead  colic,  painter's  colic — true  colic  with  marked 
constipation.  The  patient  is  relieved  by  pressure  upon  the 
abdomen  and  will  often  be  found  lying  prone  upon  a  pillow  or 
bolster.  Mosse  found  that  the  injection  of  lead  acetate  into  ani- 
mals caused  degenerative  changes  in  the  sympathetic  ganglia  of 
the  abdomen,  and  it  has  generally  been  believed  that  the  con- 
stipation is  due  to  irritation  of  the  splanchnic  inhibitory  nerves  of 
the  intestine.  But  both  the  constipation  and  the  colic  are  prob- 
ably due  to  an  irregular  irritation  of  the  vagus  nerves,  the  motor 
nerves  of  the  small  intestines,  for  Oliver  found  that  in  animals 
dead  from  lead-poisoning  the  small  intestines  were  contracted 
tightly  at  irregular  intervals,  and  Hertz  noted  by  the  .r-rays  that 
the  retardation  occurs  in  the  small  intestine,  which  is  unusual  in 


LEAD  527 

constipation.  It  is  presumably  a  spastic  constipation.  In  the 
small  intestine  in  rabbits  and  cats  Hirschfelder  found  irregular 
constrictions  which  were  checked  by  atropine  and  nicotine.  The 
intestinal  arteries  were  strongly  contracted.  Vaquez  (1904) 
and  Pal  (1905)  found  the*  colic  associated  with  a  crisis  of  general 
arterial  hypertension.  Its  severity  can  be  lessened  by  atropine, 
nitrites,  opium,  or  cathartics,  the  establishment  of  coordinated 
peristalsis  apparently  aiding  in  overcoming  the  spasms.  Colic  is 
the  most  frequently  observed  of  the  striking  manifestations. 
It  is  sometimes  followed  by  a  soreness  in  the  abdomen  which  per- 
sists for  weeks. 

2.  Palsy. — The  usual  lesion  is  a  motor  neuritis  of  the  musculo- 
spiral  nerve  below  the  origin  of  the  branch  which  goes  to  the  supi- 
nator  longus.     This  causes  paralysis  of  the  extensors  of  the  fore- 
arm, with  the  exception  of  the  supinator  longus,  and  shows  in  the 
characteristic  "wrist-drop."     The  first  paralysis  may  show  in  the 
extensor  indicis  and  the  extensor  minimi  digiti,  the  extensor  meta- 
carpi  pollicis  usually  escaping.    The  intrinsic  muscles  of  the  hand 
undergo  considerable  atrophy.     The  paralyzed  muscles  show  the 
reaction  of  degeneration.     There  is  no  pain.     Though  this  is  the 
usual  lesion,  the  motor  neuritis  may  show  in  other  regions  also. 
Indeed,  it  is  prone  to  appear  in  the  limb  most  used.     In  left- 
handed  workers  it  may  appear  first  in  the  left  arm.     In  children 
it  is  usual  in  the  legs.     Starr  says  that  colic  precedes  the  palsy 
in  over  90  per  cent,  of  the  paralytic  cases. 

There  may  also  be  a  general  peripheral  neuritis  (sensory 
and  motor)  similar  to  that  from  alcohol,  with  pain  or  great 
sensitiveness  to  pressure,  ataxia,  foot-drop,  etc.  It  may  be  so 
pronounced  as  superficially  to  resemble  locomotor  ataxia,  lateral 
sclerosis,  or  anterior  poliomyelitis.  And  there  may  be  an  optic 
neuritis,  causing  temporary  or  permanent  blindness,  laryngeal 
paralysis,  or  involvement  of  any  of  the  cranial  nerves.  Gowers 
says  that  a  lateral  tremor  of  the  fingers  is  peculiar  to  lead.  In 
poisoned  cats,  Goadby  and  Legg  have  found  minute  hemorrhages 
in  the  nerves. 

3.  Encephalopathy. — This  is  a  rare  manifestation,  and  is  said 
to  be  more  frequent  in  negroes  than  in  whites.     It  may  give 
many  different  symptoms.     Intense  headache,  vertigo,  mental 
depression,  and  insomnia  are  the  most  common.     But  it  may  go 
on  to  violent  delirium,  with  convulsions  or  apoplexy,  or  may 
develop  into  dementia  paralytica.     Kehrer  says  that  lead  menin- 
gitis should  be  distinguished  from  lead  encephalopathy,  in  the 
latter  the  lesion  being  a  degeneration  of  the  vasa  vasorum  of  the 
brain  vessels.     Moleen  reports  a  lymphocytosis  in   the  spinal 
fluid. 


528  PHARMACOLOGY   AND   THERAPEUTICS 

In  addition  to  these  striking  results, -the  continued  absorp- 
tion of  lead  is  believed  to  be  a  cause  of  arteriosclerosis,  cirrhosis 
of  the  liver,  chronic  interstitial  nephritis,  and  gouty  attacks 
(by  checking  the  elimination  of  uric  acid).  In  female  workers  in 
lead  it  has  frequently  brought  on  abortion  by  causing  the  death  of 
the  fetus.  The  offspring  of  male  workers  in  lead  are  often  defi- 
cient in  size  and  vitality,  and  similar  results  have  been  obtained 
in  experiments  on  rabbits  and  fowls.  Both  diachylon  plaster  and 
lead  acetate  pills  have  been  taken  to  produce  abortion. 

After  death  from  lead  there  is  a  striking  rapidity  of  decom- 
position with  putrefactive  odor.  The  largest  amount  of  lead  is 
found  in  the  liver. 

Diagnosis. — In  a  painter,  plumber,  or  other  worker  in  lead, 
anemia,  poor  nutrition,  backache,  tremor,  weakened  grip,  a  bad 
taste  in  the  mouth,  and  loss  of  appetite  for  breakfast  are  always 
suspicious  symptoms;  and  it  is  highly  advantageous  for  the  pa- 
tient if  the  diagnosis  is  made  at  this  stage.  In  one  not  known  to 
be  working  in  lead,  the  cause  may  not  be  suspected  until  the 
characteristic  colic  or  palsy  makes  its  appearance.  Hayhurst 
reports  that  a  5  per  cent,  solution  of  sodium  sulphide  applied  to 
the  skin  usually  shows  brown  or  black  on  hands,  wrists,  and  fore- 
arms. 

In  a  well-marked  case  there  are  three  things  to  be  looked  for, 
viz.,  lead  in  feces  or  urine,  degenerated  red  cells,  and  a  lead  line 
on  the  gums.  Lead  is  frequently  but  not  always  found  in  the 
feces  and  sometimes  in  the  urine.  Degenerative  stippling  or 
polychromatophilia  in  the  red  cells  was  found  by  Oliver  in  60 
per  cent,  of  cases.  It  is  probably  a  rather  late  manifestation, 
for  Rambousek  found  it  in  only  one  of  seven  animals  experi- 
mentally poisoned  with  lead  acetate,  and  in  painters  Harris,  of 
the  Division  of  Industrial  Hygiene,  rarely  found  it  in  the  early 
stages.  Liebermann  reports  a  lessened  fragility  of  the  red  cells. 

The  lead  line  on  the  gums  is  usual,  especially  if  the  teeth  are 
not  in  good  condition.  It  is  made  by  a  bluish  patch  just  within 
the  margin  of  each  gum,  and  is  usually  more  prominent  on  the 
lower  gums.  Occasionally  there  are  bluish-black  patches  on 
the  in  sides  of  the  cheeks  and  lower  lip.  If  the  teeth  are  absent 
there  is  no  lead  line. 

Treatment. — As  prophylactic  measures,  lemonade  containing 
sulphuric  acid,  keeping  the  fingers  out  of  the  mouth  and  washing 
the  hands  before  eating,  and  proper  ventilation  to  remove  the 
dust  of  lead  salts  have  proved  extremely  efficient  in  Germany 
and  England. 

Potassium  iodide  is  the  usual  remedy,  but  in  experimental 
animals  Oliver  found  that  it  did  not  increase  the  elimination  of 


COPPER  529 

lead.  It  may  be  that  potassium  iodide  acts  to  overcome  the  high 
arterial  tension,  rather  than  to  promote  elimination.  Gowers 
states  that  it  actually  increases  the  toxic  action  by  increasing 
the  solubility  of  the  metal.  Oliver  recommends  milk  in  large 
quantities,  with  the  addition  of  sulphur  to  form  the  unabsorbable 
lead  sulphide,  and  attention  to  the  bowels.  The  use  of  sulphates 
tc  form  lead  sulphate  in  the  alimentary  tract  has  been  recom- 
mended on  the  mistaken  idea  that  this  salt  is  not  absorbed. 

For  colic,  cathartics  are  indicated,  also  atropine,  warm 
baths,  heat  to  the  abdomen,  and,  in  some  cases,  opiates.  For 
the  neuritis  or  palsy  and  for  the  meningitis  the  usual  treatment 
for  such  conditions  is  called  for.  For  the  encephalopathy,  an 
ice-bag  to  the  head,  amyl  nitrite,  and  lumbar  puncture  may  be 
employed. 

COPPER 

Copper  (cuprum)  and  its  salts  have  a  peculiarly  deleterious 
action  upon  the  lower  forms  of  plant  life,  a  mere  trace  in  water, 
as  from  dragging  bags  of  copper  sulphate  through  the  water, 
being  found  sufficient  to  keep  it  free  from  algal  growth  without 
injuring  the  higher  plant  life  or  the  animal  life.  Even  contami- 
nated water  left  in  a  copper  vessel  will  after  a  time  be  found 
aseptic.  But  Clark  and  Gage  warn  against  the  assumption  that 
the  water  will  be  freed  from  bacteria  in  any  reasonable  length  of 
time,  and  they  find  that  vessels  made  of  other  metals  will  be 
just  as  effective  as  copper.  Pennington  and  associates  claim 
that  i  part  of  copper  sulphate  in  2,000,000  will  kill  typhoid  bacilli 
in  ten  hours;  but  Clark  and  Gage  find  that  even  i  in  100,000  kills 
them  only  occasionally,  and  that  copper  sulphate,  to  be  safe, 
must  be  present  in  as  much  as  i  part  in  1000. 

The  salt  regularly  employed  in  medicine  is  the  sulphate,  or 
blue-stone.  It  is  locally  astringent,  irritating,  and  even  caustic. 
Its  taste  is  harsh  and  strongly  metallic,  and  when  it  is  swallowed 
it  irritates  the  stomach  and  causes  vomiting. 

Uses. — Sticks  made  of  copper  sulphate  are  used  as  an  astrin- 
gent and  caustic  for  exuberant  granulations  and  granulated 
eyelids.  A  solution  of  5  to  15  grains  in  an  ounce  is  used  locally 
in  conjunctivitis,  urethritis,  and  vaginitis.  Ten  grains  (0.7  gm.) 
in  solution  have  been  used  as  an  emetic,  but  if  it  is  not  promptly 
vomited  it  may  injure  the  stomach.  It  is  recommended  in 
dose  of  |  to  i  grain  (0.015-0.06  gm.)  in  actinomycosis  and 
sporotrichosis.  Claims  made  for  copper  salts  as  remedies  for 
tuberculosis  have  not  been  substantiated. 

Toxicology. — Acute  poisoning  is  that  of  an  irritant,  and  is 
usually  checked  by  the  prompt  vomiting  of  the  drug.  Chronic 


530  PHARMACOLOGY   AND   THERAPEUTICS 

poisoning  occurs  especially  in  brass  workers,  the  symptoms 
resembling  those  of  poisoning  by  other  metals.  Even  the  minute 
amounts  used  to  color  canned  vegetables  may  be  deleterious. 

ZINC 

The  zinc  (zincum)  salts  fall  into  two  distinct  classes,  viz.,  those 
which  are  irritant  locally,  and  those  which  are  soothing  locally. 

The  irritant  salts  are  the  sulphate  and  the  chloride.  Their 
action  resembles  that  of  copper  sulphate.  The  sulphate  is  em- 
ployed in  i  to  5  per  cent,  solution  in  urethritis,  vaginitis,  and 
conjunctivitis.  To  produce  vomiting  the  dose  is  30  grains  (2  gm.) . 
The  chloride  is  also  caustic,  but  its  chief  use  is  in  i  per  cent, 
solution  as  an  odorless  disinfectant. 

The  soothing  salts  are  the  stearate,  which  is  a  light,  fluffy, 
rather  greasy,  white  powder,  and  the  oxide  and  carbonate,  which 
are  heavy  white  powders.  They  are  insoluble  in  water  and  very 
slightly  astringent,  and  are  of  value  as  soothing  protectives  to 
inflamed  surfaces.  They  may  be  employed  in  lotion  or  oint- 
ment form,  or  as  dusting-powders  in  chafed  or  inflamed  skin,  as 
in  eczema  or  dermatitis.  They  are  rarely  used  internally,  as 
they  tend  to  form  the  irritant  chloride. 

Zinc  ointment,  a  20  per  cent,  admixture  with  benzoinated 
lard,  is  very  widely  employed,  either  by  itself  or  as  a  vehicle 
for  other  drugs  in  the  treatment  of  the  skin.  Calamine,  a  natural 
impure  carbonate  of  zinc,  is  red  from  the  presence  of  iron,  and 
sometimes  slightly  gritty.  The  official  precipitated  carbonate 
of  zinc,  which  is  white,  is  a  pure  form.  Calamine  lotion  (un- 
official) is  a  mixture  of  zinc  oxide,  calamine,  glycerin,  lime-water, 
and  rose-water. 

The  oxide  and  the  sulphate  in  2-grain  (0.15  gm.)  doses  were 
at  one  time  employed  in  epilepsy,  chorea,  whooping-cough, 
and  other  spasmodic  nervous  affections,  but  are  scarcely  used 
internally  at  present. 

Zinc  chills  (spelter  chills,  brass  chills,  brass  shakes,  brazier's 
chills,  brass  founder's  ague)  occur  where  zinc  is  volatilized  and 
usually  after  work  is  over,  probably  because  sweating  stops. 
Their  appearance  is  favored  by  indulgence  in  alcohol.  After  a 
period  of  lassitude,  dull  headache,  oppression  in  the  chest  and 
sometimes  nausea,  the  chill  comes  on  with  muscular  pains,  the 
temperature  rising  as  high  as  103°  F.  The  chill  subsides  with 
the  onset  of  profuse  sweating,  zinc  being  eliminated  in  urine  and 
feces.  Swelling  of  the  spleen  and  albumin  in  the  urine  are 
reported,  but,  as  a  rule,  the  shakes  are  looked  upon  merely  as  an 
inconvenience  and  are  not  often  reported  to  a  doctor  (U.  S. 
Bureau  of  Mines,  Bulletin  73). 


BISMUTH  531 

BISMUTH 

The  bismuth  (bismuthum)  salts  commonly  employed  are  the 
subcarbonate  and  the  subnitrate,  which  are  white,  and  the  sub- 
gallate,  which  is  yellow.  Dose,  30  grains  (2  gm.).  The  sub- 
nitrate  is  crystalline,  the  subcarbonate  and  the  subgallate  are 
amorphous.  They  are  insoluble  in  water,  are  very  slightly  as- 
tringent, and  resemble  in  their  action  the  soothing  salts  of  zinc. 
But  their  chief  use  is  in  the  alimentary  tract,  where  they  do 
not  form  irritant  compounds.  The  milk  of  bismuth  (magma  bis- 
muthi),  dose,  5j  (4  c.c.),  is  also  official. 

They  act  in  a  purely  mechanical  manner  as  protectives  and 
demulcents  to  the  mucous  membrane  of  both  stomach  and  bowels. 
It  has  been  ascertained  that  if  given  before  irritant  emetics, 
they  can  prevent  vomiting.  The  author  has  in  a  number  of 
instances  given  bismuth  subnitrate  with  a  test-breakfast,  and 
has  usually  at  the  end  of  the  hour  found  a  much  lessened  secre- 
tion or  acidity.  In  a  few  cases  the  gastric  secretion  was  not 
changed  by  the  bismuth.  It  is  noteworthy  that  at  the  end  of 
the  test-breakfast  hour  the  bismuth  salt  was  uniformly  mixed 
with  the  extracted  stomach  contents,  and  that  it  had  changed 
from  a  heavy  powder  to  a  flocculent  substance  that  settled  slowly 
with  the  food.  Several  hours  after  its  administration  to  dogs 
the  author  found  the  bismuth  subnitrate  in  this  same  flocculent 
state,  and  coating  the  mucous  membrane  very  uniformly  as 
far  as  the  ileocecal  valve.  In  the  colon  the  bismuth  salt  becomes 
black  from  the  formation  of  the  sulphide  or  from  reduction,  and 
renders  the  stools  black.  As  the  sulphide  forms  hard  crystals, 
it  sometimes  acts  as  an  irritant. 

The  bismuth  salts  have  come  into  very  extensive  use  in 
#-ray  work,  their  opacity  to  the  rays  making  it  easy  to  obtain 
pictures  of  the  whole  alimentary  tract.  The  subcarbonate,  the 
oxide,  and  the  oxychloride  are  employed  for  this  purpose  by 
mouth  or  rectum,  in  amounts  of  2  to  4  ounces  (60-1 20  gm.),  mixed 
with  zoolak,  buttermilk,  thick  soup,  etc.  The  subnitrate  is  no 
longer  employed  in  these  large  amounts,  as  a  number  of  cases  of 
bismuth  and  nitrite  poisoning  have  occurred  from  its  use.  Boehme 
showed  that  bismuth  subnitrate,  when  mixed  with  human  feces, 
liberated  nitrites. 

In  one  x-ray  case  of  the  author's  two  very  large  bismuth  balls 
formed  in  the  colon  and  had  to  be  broken  up  in  the  rectum  before 
they  could  be  extracted. 

Toxicology. — From  the  local  application  to  extensive  burns, 
from  the  injection  into  tuberculous  sinuses,  and  from  the  use  of 
it  for  x-ray  pictures,  bismuth  has  been  the  cause  of  poisoning. 


532  PHARMACOLOGY   AND   THERAPEUTICS 

Its  symptoms  resemble  largely  those  of  poisoning  by  the  other 
heavy  metals,  and  are:  salivation  and  stomatitis,  with  a  black, 
violet,  or  blue-gray  line  on  the  gums,  nausea,  vomiting,  diarrhea, 
signs  of  kidney  and  colon  irritation,  convulsions,  and  collapse. 
Baehr  and  Mayer  found  considerable  amounts  of  bismuth  in 
liver,  spleen,  kidneys,  and  large  intestine,  and  Rosenbloom  found 
it  in  the  urine.  Davis  and  Kaufmann  (1910)  report  a  black  line 
on  the  gums  in  6  out  of  25  cases  in  which  bismuth  had  been 
injected  into  tuberculous  sinuses  or  joints.  One  fatal  case 
occurred  from  less  than  one  ounce  of  the  33  per  cent,  paste. 
For  such  poisoning  Beck,  who  was  the  originator  of  the  bis- 
muth treatment  for  sinuses,  recommends  to  flood  the  sinus 
or  cavity  with  warm  olive  oil  and  let  it  remain  for  twenty- 
four  hours,  and  to  wash  the  sinus  with  olive  oil  daily  thereafter 
until  the  symptoms  have  subsided.  He  advises  that  the  gums 
should  be  watched  for  the  blue  or  black  line,  which  is  the  first 
sign  of  poisoning. 

Therapeutics. — Beck's  method  of  treatment  of  chronic  sinuses 
or  tuberculous  cavities  is  to  inject,  not  oftener  than  once  a  week, 
a  33  per  cent,  paste  of  bismuth  subnitrate  with  vaseline.  He 
advises  against  it  in  acute  cases,  or  when  fresh  surfaces  have  been 
opened  up  by  probing  or  cutting. 

Internally,  the  insoluble  bismuth  salts  are  used:  (i)  To  check 
nausea,  vomiting,  and  gastric  irritation,  as  in  ulcer,  marked 
hyperchlorhydria,  and  gastric  intolerance.  (2)  To  check  intestinal 
irritation,  either  that  of  fermentative  diarrhea  or  that  from  in- 
flammation of  small  intestine  or  colon.  The  soluble  bismuth 
salts,  such  as  the  citrate,  have  no  value  in  medicine  unless  the 
bismuth  is  precipitated  from  them  in  the  alimentary  tract. 

Of  the  "milk  of  bismuth,"  a  white  suspension,  Hulse  (1910) 
reports  that  in  21  infants  with  gastro-enteritis  it  passed  through 
the  alimentary  tract  unchanged  and  without  effect;  while  inside 
of  twenty-four  hours  bismuth  subnitrate  resulted  in  diminished 
blood  and  mucus  and  fewer  stools,  and  showed  by  the  dark 
color  of  the  stools  that  it  had  undergone  change. 

CERIUM 

The  official  salt  of  cerium  (cerium)  is  the  oxalate,  Ce2(C2O.i)2.- 
ioHoO,  an  inert  powder,  insoluble  in  water.  The  commercial 
article  is  very  impure.  Its  action  is  practically  that  of  the  in- 
soluble bismuth  salts  in  allaying  gastric  and  intestinal  irrita- 
tion, but  its  therapeutic  use  is  mostly  to  check  nausea  and  vomit- 
ing. Baehr  and  Wessler  (1909)  found  it  non-poisonous  to  dogs 
even  in  closes  of  50  grams  (if  oz.).  They  noted  also  that  its 


SILVER  (ARGENTUM)  533 

action  was  mechanical  as  a  protective  to  the  gastric  mucous 
membrane,  and  that  it  would  check  the  vomiting  from  stomach 
irritants;  but  that  it  had  no  influence  on  the  vomiting  brought 
about  by  apomorphine,  which  is  a  central  emetic.  They  found 
the  usual  dose  entirely  too  small  for  protective  purposes,  and 
recommend  doses  of  30  to  60  grains  (2-4  gm.).  A  mixture  of 
cerium  oxalate,  5  grains  (0.3  gm.),  and  sodium  bicarbonate, 
10  grains  (0.7  gm.),  has  frequently  been  employed  in  refractory 
cases  of  nausea  and  vomiting,  as  in  pregnancy.  It  may  be  given 
with  water,  or  added  to  a  glass  of  milk  and  the  milk  fed  in 
small  quantities  at  a  time. 

SILVER    (ARGENTUM) 

The  official  salt  employed  is  silver  nitrate,  a  crystalline  salt 
which  is  decomposed  by  oxidizable  organic  matter  and  light, 
and  is  soluble  in  less  than  its  own  weight  of  water.  "Lunar 
caustic"  is  silver  nitrate  toughened  by  the  addition  of  hydro- 
chloric acid  to  make  a  small  amount  of  silver  chloride  (horn 
silver) ,  and  molded  into  sticks. 

Silver  nitrate  is  antiseptic  and  very  irritant  locally.  It 
coagulates  protein,  so  is  astringent,  and  may  readily  destroy 
the  soft  tissues,  so  is  caustic.  It  has  little  penetrating  power, 
and  its  action  may  be  checked  very  promptly  by  sodium  chloride, 
which  changes  it  to  the  inert  silver  chloride.  Wildbolz  (1907), 
by  reduction  with  the  Finsen  light,  found  that  i  :  1000  to  i  :  100 
solutions  penetrated  to  the  subepithelial  tissue  of  a  dog's  urethra, 
while  i  to  3  per  cent,  solutions  of  protargol  had  less  penetrating 
power. 

In  2  per  cent,  solution  silver  nitrate  is  used  as  a  prophylactic 
against  gonorrheal  ophthalmia  in  the  newborn  (Crede's  method). 
In  0.5  to  5  per  cent,  solution  it  is  employed  in  nose  and  throat, 
or  for  cracked  nipples  or  canker  sores  or  ulcers,  and  in  o.i  to  i 
per  cent,  solution  for  the  conjunctiva,  vagina,  urethra,  bladder,  or 
rectum  in  various  infections. 

The  lunar  caustic  is  employed  to  destroy  exuberant  granu- 
lations, to  remove  small  neoplasms,  warts,  condylomata,  etc., 
and  to  stimulate  the  surface  of  a  sluggish  ulcer  or  sore.  To  re- 
move a  wart  the  pointed  caustic  stick  is  moistened  and  bored 
down  into  the  central  artery  of  the  wart.  The  wart  turns  black 
and  may  be  removed  in  a  few  days. 

In  the  stomach,  the  nitrate  has  been  employed  in  hyper- 
chlorhydria  and  chronic  gastritis;  but  as  it  is  immediately 
rendered  inert  by  hydrochloric  acid  or  sodium  chloride,  it  is 
useless  unless  preceded  by  thorough  lavage.  If  it  is  employed 


534  PHARMACOLOGY    AND    THERAPEUTICS 

at  all,  the  best  method  is  to  administer  it  in  i  :  500  solution 
through  the  lavage  tube,  and  then,  after  two  or  three  minutes, 
to  remove  it  by  thorough  lavage.  If  it  is  desired  to  give  silver 
nitrate  in  pills,  kaolin  and  petrolatum  should  be  employed  in 
their  manufacture,  for  extracts,  glucose,  glycerin,  and  other 
organic  excipients  will  render  the  nitrate  inert. 

In  the  bowel,  it  has  much  local  employment  in  colitis  and 
proctitis.  Rogers  found  that  in  aqueous  solution  i  :  10,000 
killed  the  dysentery  bacillus  in  five  minutes,  but  that  in  the  pres- 
ence of  organic  matter  and  salts  it  failed  to  kill  in  a  strength  of 
i  :  100.  Not  infrequently  it  increases  the  irritation  instead  of 
curing  it. 

The  nitrate  makes  a  black  stain  on  exposure  to  light,  to 
remove  which  the  skin  may  be  washed  with  solution  of  potassium 
cyanide,  or  covered  with  tincture  of  iodine  and  washed  off  with 
solution  of  sodium  hyposulphite. 

A  number  of  organic  silver  compounds  are  also  to  be  had, 
the  most  used  of  which  are  argyrol  (silver  vitellin)  and  protargol 
(silver  protein).  Colloidal  silver,  collargol,  is  also  employed 
by  mouth  in  dose  of  45  grains  (3  gm.),  by  inunction  with  a 
15  per  cent,  ointment,  and  intravenously  for  septic  conditions 
in  doses  of  2  drams  (8  c.c.)  of  a  2  per  cent,  solution.  Dunger 
has  shown  that  an  intravenous  of  collargol  suspension  caused  a 
prompt  destruction  of  40  to  80  per  cent,  of  the  circulating  leuco- 
cytes, but  stimulated  the  bone-marrow  so  that  in  twelve  hours 
the  leucocyte  count  was  restored.  These  preparations  are  not 
essentially  astringent,  and  are  not  precipitated  by  albumin  and 
chlorides.  As  argyrol  and  collargol  are  non-irritant,  and  pro- 
targol only  slightly  irritant,  they  have  come  into  very  extensive 
use  to  replace  silver  nitrate.  Comparative  studies  of  the  relative 
antiseptic  values  of  the  silver  preparations  show  that  the  only 
one  with  pronounced  germicidal  effect  in  aqueous  solution  is  the 
silver  nitrate;  but  that  albuminous  substances,  as  in  serum  and 
the  tissues,  quickly  destroy  its  antiseptic  power.  In  Rogers 
experiments  with  the  dysentery  bacillus,  albargin  (silver  gela- 
tose)  gave  the  best  results  in  the  presence  of  organic  matter  and 
salts.  Marshall  and  Neave  have  shown  that  the  percentage  of 
silver  does  not  indicate  the  antiseptic  value. 

Derby  (1906)  tested  a  staphylococcus  on  a  mixture  of  hydro- 
cele  fluid  and  bovine  serum.  With  an  equal  volume  of  2  per 
cent,  silver  nitrate  he  could  still  obtain  a  growth  after  thirty  to 
forty  minutes;  with  an  equal  volume  of  8  per  cent,  protargol,  a 
growth  after  sixty  minutes;  and  with  50  per  cent,  argyrol,  an 
abundant  growth  after  three  and  one-half  hours. 

Bayard  Clark  and  Wylie  (1911)   report  an  extensive  series 


ALUMINIUM  (ALUMINUM) 


535 


of  comparative  bacteriologic  studies,  from  which  we  take  the 
following  as  examples: 


ORGANISM 

SOLUTION 

NUMBER  OF  COLONIES  FROM  ONE 
LOOPFUL  TAKEN  AFTER 

S  minutes 

15  minutes 

30  minutes 

Streptococcus.  .  . 
Gonococcus  

2  per  cent,  silver  nitrate  .  . 
i  per  cent,  silver  nitrate  .  . 
10  per  cent,  protargol  

O 

6 

25 
O 

4 
IS 

o 

O 

30 
70 
80 

O 

5 

20 
O 
O 

8 

0 

o 

25 
50 

100 

O 

o 

20 
o 

0 
0 

o 
o 
IS 

10 

IS 

30  per  cent,  argyrol  

10  per  cent,  argyrol  

2.5  per  cent,  collargol  

i  :  5000  silver  nitrate  .  . 

i  :  1000  silver  nitrate  

10  per  cent,  protargol  

30  per  cent,  argyrol  

2.5  per  cent,  collargol  .... 

These  might  be  compared  with  the  table  given  under  Disin- 
fectants, page  490. 

Untoward  effects  of  silver  are:  (i)  argyria,  a  bluish  staining  of 
the  skin  which  is  permanent.  It  may  appear  in  spots  (the 
"spotted  boy"  of  the  circus).  It  usually  was  the  result  of  the 
now  obsolete  treatment  of  epilepsy  and  other  nervous  diseases 
with  silver  nitrate.  It  is  reported  from  the  use  of  collargol. 

(2)  There  is  also  at  times  from  the  local  use  in  the  eye  a  con- 
junctival  argyria.  According  to  Theobold,  this  is  more  common 
from  the  organic  compounds  than  from  the  nitrate. 

Collargol  and  argyrol  solutions  are  employed  for  injection 
into  the  ureters  to^obtain  #-ray  pictures  of  the  ureter  and  kidney 
pelvis. 

ALUMINIUM    (ALUMINUM) 

Alum  (alumen,  aluminis)  of  the  Pharmacopoeia  is  potas- 
sium alum,  the  double  sulphate  of  aluminium  and  potassium, 
KAl(SO4)2.i2H2O,  or  ammonium  alum,  NH4Al(SO4)2.i2H2O.  It 
is  soluble  in  about  9  parts  of  water  and  insoluble  in  alcohol.  Its 
taste  is  sour,  and  it  is  decidedly  astringent  by  coagulation  of  the 
proteins  of  the  superficial  cells,  but  it  is  not  very  irritant.  It 
is  a  constituent  of  some  baking-powders,  but  is,  without  much 
doubt,  harmful  to  digestion. 

It  is  employed,  usually  in  5  per  cent,  solution,  as  a  gargle 
or  spray  in  relaxed  sore  throat,  as  a  vaginal  douche,  and  as  a  wash 
for  the  skin  to  stop  local  sweating  of  the  hands  and  feet  or  the 


536  PHARMACOLOGY  AND  THERAPEUTICS 

night-sweats  of  tuberculosis.  The  crystals  may  be  used  to 
shrink  canker  sores  in  the  mouth,  or  to  check  hemorrhage  from 
scratches  or  small  cuts.  The  powdered  alum  has  been  used 
in  6o-grain  (4  gm.)  dose  as  an  emetic,  but  is  not  at  all  reliable. 

Burnt  alum  (alumen  exsiccatum)  is  alum  with  the  water  of 
crystallization  driven  off  by  heat.  It  has  a  great  affinity  for 
water,  is  powerfully  astringent,  and  is  slightly  caustic.  Its 
chief  employment  is  as  an  application  to  sluggish  ulcers. 

The  solution  of  aluminium  subacetate,  N.  F.,  is  made  by  acting 
on  calcium  acetate  with  aluminium  sulphate  in  solution,  the  in- 
soluble calcium  sulphate  being  removed  by  nitration.  The  solu- 
tion of  aluminium  acetate,  N.  F.  (Burow's  solution)  is  prepared 
by  mixing  solutions  of  alum,  12.6  gm.,  and  lead  acetate,  15  gm., 
and  adding  water  enough  to  make  100  c.c.  The  precipitate  of  lead 
sulphate  is  filtered  off,  as  poisoning  has  occurred  from  failure  to 
remove  this.  Either  formula  makes  a  slightly  astringent,  slightly 
antiseptic  liquid,  the  chief  use  of  which  is  as  a  wet  dressing  for 
infected  wounds.  Koll  (1912)  reports  great  success  with  it  also 
in  42  cases  of  colon  bacillus  infection  of  the  urinary  tract. 

A  25  per  cent,  solution  of  aluminium  chloride  may  be  applied 
every  two  or  three  days  for  sweating  of  hands,  feet,  or  axillae. 
It  is  irritant  and  may  cause  a  dermatitis. 


IRON 

There  are  many  official  preparations  of  iron  (ferrum),  but 
a  knowledge  of  only  seven  or  eight  will  give  a  good  equipment 
for  iron  therapy.  (Those  made  in  our  laboratory  were  the  syrup 
of  ferrous  iodide,  the  solution  of  ferric  chloride,  the  tincture  of 
ferric  chloride,  the  liquor  ferri  et  ammonii  acetatis,  Blaud's  pills 
of  ferrous  carbonate,  and  the  arsenic  antidote  of  ferric  hydroxide 
with  magnesia.) 

There  are  four  main  uses  in  medicine  for  preparations  of 
iron,  as  follows: 

1 .  Disinfectant. — Ferrous  sulphate  (copperas) ,  for  sinks,  water- 
closets,  cess-pools,  etc.     It  is  cheap,  but  not  very  effective. 

2.  Astringent. — The  ferrous  and  ferric  salts  of  the  mineral 
acids,  especially  the  sulphates,  the  subsulphates,  and  the  chlo- 
rides, precipitate  protein,  are  strongly  astringent,  and  coagulate 
the  blood.     They  are  also  irritant.     A  mixture  of  equal  parts  of 
the  tincture  of  ferric  chloride,  glycerin,  and  water  is  a  favorite 
application  in  sore  throat;  it  is  astringent  and  irritant;  it  may 
attack  the  teeth.     The  use  of  these  astringent  preparations  in 
nose-bleed  and  other  small  hemorrhages   (the  styptic  action) 
results  in  a  dirty  coagulum  and  irritation  of  the  tissues,  and  it 


IRON  537 

has  practically  been  abandoned.  Liquor  ferri  chloridi,  liquor 
jerri  subsulphatis  (Monsel's  solution),  and  liquor  ferri  tersulphatis 
are  official. 

3.  Arsenic  Antidote. — The  freshly  precipitated  ferric  hydrox- 
ide changes  the  active  arsenows  preparations  into  the  compara- 
tively inactive  and  insoluble  arsem'c  compounds  of  iron.    Arny 
gives  the  reaction  with  arsenous  acid  as:  3As2O3  -f  2Fe(OH)3  = 
2Fe(AsO2)3  +  3H2O.     Ferric  hydroxide  as  an  antidote  may  be 
administered  in  large  quantity,  after  which  it  must  be  washed 
out  of  the  stomach  without  delay  to  remove  the  arsenic  compound 
formed. 

Ferri  hydroxidum  cum  magnesii  oxido  is  made  with  a  mixture 
of  magnesium  oxide  and  water,  and  may  be  given  freely. 

MgO  +  H20  =  Mg(OH)2 
Fe2(S04)3  +  3Mg(OH)2  =  2Fe(OH)3  +  3MgSO4 

It  is  not  necessary  to  wash  out  the  magnesium  sulphate. 

Ferric  hydroxide  may  also  be  made  by  precipitating  the  solu- 
tion of  ferric  sulphate  or  ferric  chloride  with  ammonia  water, 
filtering,  and  washing  the  precipitate  with  water  to  remove  the 
ammonium  sulphate. 

4.  Hematinic,  tending  to  increase  the  hemoglobin  content  of 
the  blood.    The  hematinics  may  be  separated  into  six  varieties: 

(a)  Metallic  Iron  (Ferrum  Reductum;  Reduced  Iron}. — Dose, 
i  grain  (0.06  gm.).     It  is  a  fine,  grayish-black  powder,  made  by 
reducing  ferric  oxide  with  hydrogen.     It  consists  of  not  less  than 
90  per  cent,  pure  iron,  and  requires  acid  in  the  stomach  for  its 
solution. 

(b)  The  Inorganic  Ferrous  Salts. — They  are:  The  carbonate 
in  the  saccharated  carbonate,  massa  ferri  carbonatis  (Vallet's 
mass),  and  pilula  ferri  carbonatis  (Blaud's  pills);  the  iodide  in 
pills  of  ferrous  iodide  and  syrup  of  ferrous  iodide,  dose,  15  minims 
(i  c.c.);  the  sulphate,  dose,  3  grains  (0.2  gm.);  the  dried  sulphate, 
dose,  2  grains  (0.13  gm.) ;  the  latter  in  pills  of  aloes  and  iron,  each 
containing  i  grain  (0.06  gm.). 

(c)  The    Inorganic   Ferric   Salts. — These   are    the   chloride, 
dose  of  the  tincture,  5  minims  (0.3  c.c.) ;  and  the  phosphate,  dose, 
4  grains  (0.25  gm.).     The  elixir  and  the  syrup  of  the  phosphates 
of  iron,  quinine,  and  strychnine,  dose,  2  drams  (8  c.c.),  are  no 
longer  pharmacopceial.    These  mineral  salts  are  astringent,  irritat- 
ing to  the  stomach,  and  constipating.     In  liquid  form  they  tend 
to  blacken  the  teeth  and  to  injure  the  enamel.     To  protect  the 
teeth  the  dose  should  be  well  diluted,  taken  through  a  tube,  and 
followed  by  rinsing  the  mouth.     The  tincture  of  the  chloride 
contains  free  acid  and  is  especially  destructive  to  the  teeth. 


538  PHARMACOLOGY   AXD   THERAPEUTICS 

(d)  The  Salts  of  Organic  Acids. — These  are  the  ferric  acetate, 
citrate,  and  tartrate.       U.  S.  P.  preparations  are:  Liquor  ferri 
et  ammonii  acetatis  (Basham's  mixture),  dose,  2  drams  (8  c.c.); 
and  the  soluble  double  alkaline  salt,  iron  and  ammonium  citrate. 
The  iron  and  ammonium  tartrate,  and  iron  and  potassium  tartrate, 
dose,  4  grains  (0.25  gm.),  the  citrate  of  iron  and  quinine,  dose, 
4  grains   (0.25   gm.),   containing  ^  grain  of  quinine,   and  the 
citrate  of  iron  and  strychnine,  containing  i  per  cent,  of  strych- 
nine, dose,  2  grains  (0.13  gm.),  are  no  longer  pharmacopceial. 

The  salts  of  this  group  do  not  readily  dissociate,  so  they  do 
not  readily  precipitate  proteins.  Hence  they  are  less  irritant, 
less  astringent,  and  less  constipating  than  the  salts  of  the  mineral 
acids.  Their  solutions  do  not  corrode  the  enamel  of  the  teeth. 

The  citrate  in  5  per  cent,  solution  has  been  used  hypoderm- 
atically  in  dose  of  i  grain  (0.26  gm.)  with  reported  rapid  effects. 

(e)  Artificial  Protein  (or  Organic)  Compounds. — Albuminates, 
peptonates,  etc.     Ovoferrin  is  a  liquid  purporting  to  be  made  from 
the  white  of  egg;  ferratin,  a  preparation  claimed  incorrectly 
to  be  the  natural  iron  compound  of  the  pig's  liver. 

(/)  True  "organic"  or  "masked"  iron,  sometimes  spoken  of 
as  food  iron,  as  in  hemoglobin  or  yolk  of  egg. 

Absorption. — To  prevent  irritation  of  the  stomach,  iron  prep- 
arations are  regularly  administered  after  meals,  and  mostly  form 
the  ferrous  chloride  or  albuminate  in  the  stomach.  On  passing  to 
the  duodenum,  the  chloride  or  sulphate  probably  changes  to  the 
carbonate.  After  a  meal  containing  an  added  iron  salt,  granules 
of  iron  are  found  in  the  epithelium  and  leukocytes  of  the  duodenal 
mucous  membrane  and  in  no  other  portion  of  the  alimentary  tract 
(Macallum).  But  after  an  iron-nuclein  compound,  Cloetta 
found  it  also  in  the  membrane  much  further  down  the  small  intes- 
tine. It  enters  the  blood  probably  either  as  the  albuminate  or 
carbonate.  There  seems  to  be  no  essential  difference  in  absorb- 
ability between  the  inorganic  and  organic  forms  of  iron.  The 
spleen  does  not  exert  any  constant  or  important  influence  on 
the  iron  metabolism.  Even  in  the  absence  of  the  spleen  a 
sufficient  supply  of  iron  results  in  normal  blood  conditions. 

A  medicinal  dose  of  an  iron  salt  is  3  to  5  grains,  but,  as  has 
been  shown  by  severing  the  intestine  above  the  cecum,  almost  all 
of  this  passes  through  the  alimentary  tract  unabsorbed.  Some  of 
it  forms  the  sulphide,  and  this  may  give  a  dark  or  blackish  color 
to  the  feces.  Iron  that  is  absorbed  but  does  not  enter  into  hemo- 
globin or  some  other  natural  organic  compound  is  a  foreign  sub- 
stance and  is  poisonous. 

The  Absorbed  Iron. — This  passes  into  the  portal  blood  and 
perhaps  slightly  into  the  lymph,  and  is  soon  found  deposited  in 


IRON  539 

the  spleen  and  mesenteric  lymph-nodes  and  slightly  in  the  liver 
cells  and  the  cells  of  the  convoluted  tubules  of  the  kidney.  Later 
it  is  found  in  greatest  abundance  in  the  bone-marrow  and  liver, 
and  still  later  appears  in  the  epithelium  of  the  colon  and  rectum, 
where  it  is  excreted  into  the  feces.  Of  the  iron  excreted  by  normal 
persons  under  normal  conditions,  about  nine-tenths  is  excreted  in 
the  feces,  and  one-tenth  in  the  urine.  Practically  all  the  medici- 
nal iron  is  excreted  in  the  feces.  A  portion  of  the  iron  of  the 
liver  is  synthetized  into  organic  compounds  (ferratin,  etc.),  ready 
for  conversion  into  hemoglobin,  and  the  rest  is  doled  out  for  excre- 
tion. There  is  no  increase  in  the  amount  of  iron  in  the  bile. 

Effect  on  Blood. — Normally,  the  whole  adult  human  body 
contains  from  40  to  55  grains  of  iron,  enough  to  make  a  2-inch 
nail.  The  ordinary  diet  contains  -^  to  i  grain  (5  to  ib  mg.)  of 
iron  per  day,  this  minute  amount  being  sufficient  to  maintain  the 
iron  equilibrium  of  the- body.  During  the  growing  period  more 
iron  is  necessary.  In  human  milk,  between  the  third  and  twelfth 
days  of  lactation,  Cameron  found  21  mg.  of  iron  in  100  c.c. ;  while 
in  mixed  cows'  milk  Bunge  found  3.5  mg.,  and  Van  Slyke  only 
i  mg.  in  100  c.c.  Krasnogorsky  found  the  iron  of  milk  more 
readily  absorbed  than  that  of  egg-yolk  or  spinach. 

For  over  a  month  Charteris  (1903)  gave  normal  rabbits  a 
daily  hypodermatic  of  \  to  i  grain  (0.03-0.06  gm.)  of  an  albu- 
minate  of  iron.  They  maintained  health  and  gained  weight. 
There  was  no  essential  change  in  the  bone-marrow  except  a 
slight  increase  in  the  density  and  vascularity  of  the  leukoblastic 
elements.  But  healthy  mice  fed  on  cheese  and  iron  regularly 
contained  more  iron  in  their  tissues  than  control  mice  fed  on 
cheese  alone,  and  healthy  goats  fed  on  milk  and  iron  more  than 
goats  fed  on  milk  alone.  Therefore,  in  health,  though  the  ad- 
ministration of  iron  results  in  some  accumulation  of  iron  either 
free  in  the  blood  or  stored  up  in  the  liver,  spleen,  etc.,  it  is  not  fol- 
lowed in  adults  by  any  notable  increase  in  either  the  hemoglobin 
or  the  red  cells,  and  the  iron  is  in  a  sense  a  foreign  body;  that  is,  it 
does  not  go  to  form  blood,  and  there  is  no  plethora  established. 
But  after  bleeding,  animals  have  been  shown  to  utilize  iron  that 
was  given  them,  and  in  many  human  cases  with  hemoglobin  below 
normal  its  administration  seems  to  be  followed  by  a  greater  in- 
crease in  both  the  hemoglobin  and  the  red  cells  than  conies  from 
the  food  alone.  In  these  cases  it  is  possible  that  "under  the 
stimulus  of  iron  the  blood-forming  organs  become  active  in  the 
synthesis  of  hemoglobin"  (von  Noorden).  Kleinschmidt  found 
that  growing  dogs  had  a  much  greater  power  than  adults  to 
utilize  iron  given  with  the  food. 

Hemoglobin  itself,  as  in  raw  blood  or  uncooked  meat,  is  con- 


540  PHARMACOLOGY   AND   THERAPEUTICS 

verted  by  the  gastric  juice  to  acid  hematin,  and  when  taken  by 
man  is  believed  to  be  mostly  unabsorbed.  It  has  been  ascertained 
that  i  c.c.  of  blood  by  mouth  will  give  a  test  in  the  feces.  How- 
ever, Halliburton's  experiments  with  raw  blood  on  rats  fed  on  an 
otherwise  iron-poor  diet,  showed  a  slight  increase  in  the  red  blood- 
corpuscles  and  hemoglobin  of  the  blood,  and  the  presence  of 
absorbed  iron  in  the  cells  of  the  duodenal  mucous  membrane. 

In  cooked  blood,  as  in  cooked  meat,  the  hemoglobin  is  changed 
and  is  absorbed  more  readily,  but  even  then  not  readily. 

Toxicology. — In  excessive  amounts  iron  may  produce  nausea, 
vomiting,  constipation,  and  headache.  Dixon  says  that  if  it  is 
administered  intravenously  it  is  as  toxic  as  arsenic.  In  very  large 
quantities  the  irritant  inorganic  salts  may  cause  great  irritation 
of  stomach  and  bowels,  with  collapse.  There  is  no  satisfactory 
evidence  that  excess  of  iron  has  any  power  to  increase  a  hemor- 
rhagic  tendency  or  to  bring  on  plethora. 

Therapeutics. — The  therapeutic  classification  given  above 
indicates  its  uses.  As  a  hematinic  it  may  be  employed  in  all  con- 
ditions with  diminished  hemoglobin.  Its  most  prompt  effects  are 
seen  in  chlorosis,  but  good  results  may  also  follow  its  use  in  the 
secondary  anemias.  It  is  best  given  in  conjunction  with  appe- 
tizers, tonics,  laxatives,  etc.,  according  to  need.  In  nephritis  the 
anemia  is  often  treated  with  iron,  especially  Basham's  mixture, 
but  there  is  no  satisfactory  evidence  of  any  direct  effect  upon  the 
kidneys  or  upon  the  excretion  of  albumin.  It  has  been  employed 
also  in  functional  albuminuria,  and  there  is  a  traditional  belief 
that  it  will  cure  this  condition.  The  citrate  has  been  used  hypo- 
dermatically,  in  5  or  10  per  cent,  solution,  in  dose  of  i  grain  (0.06 
gm.)  daily.  It  is  readily  absorbed. 

MANGANESE 

Though  found  in  the  tissues  in  minute  quantity,  manganese 
is  not  essential  to  life,  and  does  not  form  an  integral  part  of  any 
protein  molecule.  Bertrand  and  Megreccann  claim  that  man- 
ganese acts  as  a  catalytic  agent  for  iron,  an  almost  infinitesimal 
amount  causing  an  increased  absorption  and  utilization  by  the 
tissues.  In  anemia  it  is  sometimes  given  with  iron,  e.  g.,  in  the 
form  of  a  peptonate  or  albuminate. 

Manganese  dioxide,  dose,  2  grains  (0.013  gm.),  and  potassium 
permanganate,  dose,  i  grain  (0.06  gm.),  are  official  and  have  a 
reputation  as  emmenagogues.  Potassium  permanganate,  through 
its  oxidizing  powers,  is  locally  antidotal  to  morphine,  and  in 
i  :  10.000  to  i  :  1000  aqueous  solution  has  considerable  value  as 
an  antiseptic  and  deodorizer.  In  India  it  has  been  found  useful 
locally  in  snake-bite,  and  it  is  recommended  by  von  Adelung  in 


ARSENIC  (ARSENUM)  541 

ivy-poisoning.  Calcium  permanganate,  a  less  irritating  compound, 
is  used  by  Rogers  for  colon  irrigations  in  amebic  dysentery.  He 
uses  15  grains  (i  gm.)  to  a  pint  (480  c.c.). 

Chronic  poisoning  occurs  in  workers  in  zinc  mines,  manganese 
grinding  mills,  and  among  those  making  potassium  permanganate. 
Great  muscular  weakness,  a  coarse  intention  tremor,  muffled 
speech,  and  depressed  cerebration  are  the  most  striking  features. 
In  some  cases  there  is  pronounced  hysteria.  The  treatment 
consists  of  hydrotherapy,  electricity,  and  physical  exercises. 

ARSENIC    (ARSENUM) 

Arsenic  is  widely  distributed  in  nature  and  can  be  detected  in 
many  of  our  commonly  used  chemicals  and  even  in  certain  chemic 
drugs.  It  is  said  to  appear  in  the  fruit  of  trees  sprayed  with  Paris 
green,  and  in  other  plants  grown  in  the  soil  where  Paris  green 
has  been  used. 

Preparations  and  Doses. — (a)  Those  of  Arsenous  Acid.— 
Arsenic  trioxide,  arsenous  acid,  white  arsenic,  As2O3,  is  an  anhy- 
dride which  occurs  as  a  practically  odorless  and  tasteless  white 
powder,  made  either  from  the  glassy  variety,  soluble  in  30  parts  of 
water,  or  from  the  porcelain  or  crystalline  variety,  soluble  in  100 
parts  of  water.  Both  dissolve  in  5  parts  of  glycerin  and  are 
sparingly  soluble  in  alcohol.  Dose,  -^  grain  (0.002  gm.). 

Solution  of  arsenous  acid,  liquor  acidi  arsenosi,  i  per  cent.,  is 
acid  with  hydrochloric  acid.  Dose,  3  minims  (0.2  c.c.). 

Fowler's  solution,  liquor  potassii  arsenitis,  KAsO2.HAsO2.H2O, 
i  per  cent.,  contains  the  compound  tincture  of  lavender  to  give 
it  distinctive  odor,  taste,  and  color  as  a  preventive  against 
accidents.  Dose,  3  minims  (0.2  c.c.).  This  is  the  favorite 
liquid  preparation.  It  is  incompatible  with  acids,  and  tends  to 
oxidize  and  deteriorate. 

Arsenous  iodide,  AsI3;  dose,  ^  grain  (0.005  g111-)- 

Donovan's  solution,  liquor  arseni  et  hydrargyri  iodidi,  contains 

1  per  cent,  each  of  arsenous  iodide  and  mercuric  iodide.     Dose, 

2  minims  (0.12  c.c.). 

(b)  Those  of  Arsenic  Acid. — Sodium  arsenate,  Na2HAsO4,- 
7H2O;  close,  TV  grain  (0.005  gm-)- 

Dried  sodium  arsenate,  sodii  arsenas  exsiccatus,  is  sodium 
arsenate  deprived  of  its  water  of  crystallization  by  heat.  As  this 
water  constitutes  about  two-fifths  of  the  arsenate,  the  drying 
nearly  doubles  the  strength.  Dose,  •£$  grain  (0.003  gm.). 

Solution  of  sodium  arsenate,  i  per  cent,  of  the  dried  salt;  dose, 

3  minims  (0.2  c.c.). 

(c)  Besides  the  official  preparations,  there  are  a  number  of 
organic  compounds  that  are  in  use: 


542  PHARMACOLOGY   AND   THERAPEUTICS 

Sodium  arsanilate  (sodium  aminophenyl  arsonate)  is  employed 
in  the  form  of  atoxyl,  C6H4(NH2).(AsC).OH.ONa)  +  3H2O,  con- 
taining 3  molecules  of  water  of  crystallization  and  26  per  cent,  of 
arsenic;  and  soamin,  C6H4(NH2).(AsO.OH.ONa)  +  5H2O,  which 
contains  5  molecules  of  water  of  crystallization  and  2  2  per  cent, 
of  arsenic.  They  are  white  powders,  soluble  in  5  or  6  parts  of 
water,  and  decomposed  by  acids.  Because  of  the  acidity  of  the 
gastric  juice,  they  are  given  hypodermatically.  Dose,  £  to  3 
grains  (0.02-0.2  gm.)  every  second  day. 

Arsacetin  is  sodium  acetyl  arsanilate,  C6H4(NHCH3CO).- 
(AsO.OH.ONa),  soluble  in  10  parts  of  cold  water  and  3  parts  of 
hot  water.  It  can  be  sterilized  in  the  autoclave  at  130°  C.  for  one 
hour  without  decomposition.  The  claim  is  made  that  it  is  not 
split  up  by  acids.  The  hypodermatic  dose  is  3  grains  (0.2  gm.) 
two  or  three  times  a  week.  By  mouth  the  dose  is  f  grain  (0.05 
gm.)  three  or  four  times  a  day. 

Arsenophenylglycin,  As2(COOH.CH2.N.H.C6H4)2,  has  a  hypo- 
dermatic dose  of  12  grains  (0.8  gm.). 

Sodium  cacodylate,  sodium  dimethyl  arsenate,  (CH3)2AsO.- 
ONa  +  3H2O,  is  readily  soluble  in  water.  It  liberates  arsenic 
quite  slowly,  hence  is  less  toxic  and  less  active  than  the  inorganic 
salts.  Dose,  i  grain  (0.06  gm.)  hypodermatically,  or  3  grains 
(0.2  gm.)  by  mouth  daily.  A  hypodermic  of  4  to  6  grains 
(0.25-0.35  gm.),  repeated  in  four  days,  was  recommended  by  John 
B.  Murphy  in  syphilis.  Recently  doses  of  i  to  7^  grains  (0.06-0.5 
gm.)  intravenously  have  been  used  in  pernicious  anemia,  leukemia, 
and  Hodgkin's  disease.  A  number  of  other  compounds  of  caco- 
dylic  acid  have  also  been  employed,  as  those  of  iron,  mercury, 
quinine,  lithium,  etc.  Owing  to  the  formation  of  cacodyl  oxide, 
the  cacodylates  are  prone  to  give  a  garlicky  odor  to  the  breath, 
especially  when  administered  by  mouth. 

Saharsan,  Ehrlich's  "606,"  is  diamino-dihydroxy-arseno- 
benzol  dihydrochloride,  (C6H3As.OH.NH2HC])2.  It  is  a  bright 
yellow  powder,  of  strongly  acid  reaction,  and  completely  but 
slowly  soluble  in  10  parts  of  water.  It  is  used  somewhat  hypoder- 
matically, but  preferably  intravenously.  Before  use  it  must  be 
freshly  made  into  a  sterile  solution  of  slightly  alkaline  or  neutral 
reaction.  It  is  very  readily  oxidized,  so  is  kept  in  vacuo,  or  in 
ampules  filled  with  an  indifferent  gas.  The  maximum  dose  is 
10  grains  (0.6  gm.),  which  for  intravenous  use  is  dissolved  in  300 
c.c.  of  normal  saline  to  which  23  drops  of  15  per  cent,  sodium 
hydroxide  solution  arc  added.  Diarsenol,  a  recent  substitute  for 
salvarsan,  made  in  Canada,  is  claimed  to  be  the  dihydrochloride 
of  dioxydiamidoarsenobenzol,  and  is  administered  in  the  same 
way  as  salvarsan. 


ARSENIC  (ARSENUM)  543 

Neo-salvarsan,  soluble  in  water  and  of  neutral  reaction,  and 
therefore  available  by  simple  solution,  may  be  administered 
with  much  greater  ease.  It  is  sodium-diamino-dihydroxy-arseno- 
benzol-methanal  sulphoxylate  mixed  with  half  its  weight  of  inert 
substance.  Its  dose  is  if  times  that  of  salvarsan.  It  de- 
teriorates very  quickly,  so  must  be  kept  in  vacuo.  Sodium- 
salvarsan,  a  similarly  soluble  compound,  is  recommended  highly 
by  Wechselmann  and  by  Dreyfus. 

Pharmacology. — Microorganisms. — Arsenic  is  added  to  em- 
balming mixtures  to  prevent  rapid  decomposition.  It  is  more 
destructive,  however,  to  highly  organized  life  than  to  bacteria. 

Local. — Arsenic  is  irritant.  It  does  not  precipitate  protoplasm 
and  does  not  form  an  albuminate,  but  slowly  acts  on  the  tissues 
to  produce  inflammation.  An  arsenic  paste,  for  example,  causes 
pain,  redness,  and  swelling,  with  fatty  degeneration  of  the  epithe- 
lium and  inflammation  of  the  tissues  beneath.  The  inflammatory 
reaction  may  be  so  intense  that  destruction  of  tissue  follows,  with 
sloughing  and  the  formation  of  an  ulcer.  The  drug  is,  therefore, 
a  slowly  acting  and  very  painful  caustic,  which  destroys  tissue, 
not  by  precipitating  protoplasm,  but  by  inducing  an  acute  inflam- 
matory reaction.  In  its  use  to  destroy  the  nerves  of  teeth  the 
destruction  of  the  nerve  depends  upon  inflammation  and  swell- 
ing in  the  opening  of  the  root  of  the  tooth,  so  that  the  circulation 
of  the  nerve  is  cut  off. 

Alimentary  Tract. — Nausea,  vomiting,  diarrhea,  and  colic  are 
commonly  seen  from  the  use  of  arsenic.  These  effects  seem-  to  be 
produced  after  absorption,  for  they  occur  late,  and  even  when  .the 
drug  is  administered  hypodermatically.  Experimentally,  after 
large  hypodermatic  injections,  there  is  edema  of  the  intestine  from 
increased  permeability  of  the  capillaries,  with  degeneration  and 
exfoliation  of  the  intestinal  epithelium.  Arsenic-eaters  claim 
that  it  helps  the  appetite. 

Absorption  takes  place  from  the  stomach  with  fair  rapidity 
when  the  preparation  is  in  solution.  The  power  of  absorption 
may  be  rendered  less  by  repeated  doses.  (See  Tolerance.) 

Circulation. — Large  therapeutic  doses  tend  after  a  few  days  to 
produce  edema  of  the  skin  and  alimentary  tract,  as  shown  by 
puffiness  about  the  eyes  and  other  parts  of  the  body,  or  by  general 
edema,  nausea,  vomiting,  or  diarrhea.  This  is  due  to  increased 
transudation  of  serum,  from  heightened  permeability  of  the  sub- 
cutaneous and  submucous  capillaries.  In  some  cases  petechial 
(capillary)  hemorrhages  are  seen. 

The  effect  upon  the  blood-pressure  is  ordinarily  negative.  In 
severe  poisoning  the  blood-pressure  falls  from  loss  of  serum  by 
transudation,  the  heart  remaining  good. 


544  PHARMACOLOGY  AND  THERAPEUTICS 

In  chronic  poisoning  there  may  be  fatty  degeneration  of  the 
heart  and  arteries. 

Blood. — It  is  upon  the  blood  or  blood-making  organs  that 
arsenic  seems  to  exert  its  most  valuable  therapeutic  effects.  The 
normal  bone-marrow  consists  essentially  of  erythroblastic  and 
leukoblastic  elements  and  fat  cells.  When  arsenic  is  administered 
for  long  periods  to  young  growing  animals,  the  bone-marrow  be- 
comes more  vascular,  with  increase  in  the  leukocytic  elements, 
decrease  in  the  fat,  and  little  if  any  change  in  the  erythrocytic 
elements  (Charteris,  1903).  There  is  no  change  in  either  the 
number  of  red  cells  or  the  percentage  of  hemoglobin  in  the  blood. 
Besredka,  from  sublethal  doses  in  rabbits,  noted  a  temporary 
diminuticn  of  the  leukocytes  in  the  blood,  followed  by  a  poly- 
morphonuclear  leukocytosis. 

In  the  Manchester  epidemic,  in  which  over  3000  cases  of 
arsenic  poisoning  occurred  from  arsenic  in  beer,  the  cases  which 
came  to  postmortem  showed  these  changes.  But  some  of  the 
most  pronounced  cases  showed  extensive  degeneration  of  the 
marrow-cells  and  profound  anemia;  and  this  corresponded  with 
Charteris'  findings  that  "from  repeated  doses  large  enough  to 
cause  cachexia  and  emaciation  in  rabbits,  the  bone-marrow  under- 
goes hyaline  degeneration,  and  this  is  accompanied  by  decrease 
in  the  red  cells  and  hemoglobin." 

The  tendency  of  arsenic  is,  therefore,  to  increase  the  leuko- 
blastic elements  of  the  bone-marrow  and  the  leukocytes  in  the 
blood ;  but  in  severe  chronic  poisoning,  to  induce  degeneration  of 
the  marrow-cells,  wasting,  and  profound  anemia. 

In  pernicious  anemia  there  is  an  increase  in  the  erythroblastic 
elements  of  bone-marrow,  associated  with  increased  destruction 
of  red  blood-corpuscles  (hemolysis) ;  in  leukemia,  there  is  an  in- 
crease in  the  leukoblastic  elements.  In  both  of  these  conditions 
arsenic  is  employed,  at  times  with  benefit,  and  it  may  be  that  it 
acts  on  some  yet  undiscovered  toxin  or  parasite.  It  scarcely 
seems  to  be  curative,  however,  for  its  effects  do  not  last.  In 
chronic  malaria,  also,  there  is  a  destruction  of  red  cells  which  may 
be  more  or  less  checked  by  arsenic. 

Kidneys  and  Suprarenals. — Brown  and  Pearce  (1915)  tested 
60  arsenic  compounds  and  found  that  all  in  toxic  amounts  caused 
congestion  and  hemorrhage  in  the  suprarenals,  alterations  in 
the  lipoid  content,  cellular  degenerations  and  necroses,  and  reduc- 
tion in  chromaffin.  In  the  kidneys  they  obtained  varying  effects 
according  to  the  compound  used.  Arsenous  acid  produced  a 
vascular  nephritis,  arsacetin  a  tubular  nephritis,  while  salvarsan 
and  neosalvarsan  produced  a  vascular  nephritis  with  some  tubular 


ARSENIC  (ARSENUM)  545 

changes,  and  atoxyl  and  arsenophenyl-glycin  a  tubular  nephritis 
with  some  vascular  changes. 

Metabolism. — Long-continued  administration  lessens  the  ac- 
tivity of  the  liver,  so  that  it  forms  less  glycogen  and  has  less 
power  of  oxidation.  This  shows  in  the  urine  by  increased  amounts 
of  uric  acid  and  ammonia,  and  the  presence  of  leucin,  tyrosin,  and 
sarcolactic  acid,  the  total  nitrogen  of  the  urine  not  being  much 
changed.  There  may  be  a  swollen  liver  and  jaundice.  After 
a  fatal  dose  arsenic  is  usually  found  most  abundantly  in  the 
liver. 

Considerable  doses  not  only  cause  degenerative  changes  in 
the  bone-marrow,  but  have  a  strong  tendency  to  produce  fatty 
degeneration  in  the  liver,  kidneys,  heart,  arteries,  capillaries, 
the  epithelium  of  the  lungs  and  alimentary  tract,  and  striated 
muscle  and  skin  (dermis  and  epidermis) . 

Bone. — In  growing  animals  of  poor  nutrition  it  tends  to  bring 
about  an  increase  in  the  density  of  bone,  the  cancellous  portion 
being  encroached  upon  by  the  increasing  thickness  of  the  hard 
bone.  This  may  be  due  to  the  increased  vascularity  of  the  bone- 
marrow.  In  adults  there  is  probably  no  effect  on  bone. 

Epithelium. — That  it  promotes  the  nutrition  of  the  skin  and 
epithelial  tissues  is  a  general  belief,  as  indicated  by  the  sale  of 
arsenic  complexion  tonics,  by  the  frequent  administration  of 
Fowler's  solution  to  horses  to  improve  their  appearance,  and 
by  the  use  of  arsenic  in  chronic  skin  diseases.  Thomas  Oliver 
gave  a  dog  with  short,  stubby  hair  i  grain  a  day,  and  the  hair 
became  sleek  and  long  (Allbutt's  System  of  Medicine). 

Excretion. — It  is  excreted  in  the  urine  and  to  some  extent 
in  the  feces.  Traces  may  appear  in  the  gastric  juice,  the  bron- 
chial mucus,  the  sweat,  and  the  milk.  It  is  reported  as  appearing 
in  the  stomach  after  administration  by  rectum  (KandikofT) 
or  hypodermatically.  Its  elimination  is  very  slow,  and  traces 
may  be  recovered  two  or  three  weeks  after  its  administration  has 
ceased. 

Tolerance. — Among  the  mountaineers  of  Styria,  Hungary, 
and  certain  parts  of  the  Punjab  there  are  a  number  of  persons 
known  as  "arsenic-eaters."  They  live  to  old  age  and  have  no 
symptoms  attributable  to  arsenic  except  perhaps  catarrh  of  the 
upper  respiratory  passages.  Knapp  and  Buchner  saw  a  man 
who  had  had  the  habit  for  thirty-six  years  take  2.6  grains  (0.175 
gm.)  of  orpiment  (arsenic  sulphide).  Knapp  administered  7 
grains  (0.45  gm.)  of  arsenic  trioxide  to  one  of  the  arsenic-eaters 
of  Graz  without  any  effect.  Maclagan  saw  a  man  take  6  grains 
(0.4  gm.).  It  is  taken  about  once  or  twice  a  week,  and  is  said 
to  act  somewhat  like  an  intoxicant,  increasing  combativeness, 

35 


546  PHARMACOLOGY   AND   THERAPEUTICS 

stimulating  the  sexual  appetite,  and  giving  a  feeling  of  strength 
and  general  well-being. 

Besredka  injected  sublethal  doses  in  rabbits,  and  found  that 
the  leukocytes  usually  contained  arsenic,  but  not  in  the  cases 
that  proved  fatal.  He  thought  the  leukocytes  important  in 
preventing  the  poisoning.  Housmann  (1903)  found  that  in 
arsenic-habituated  dogs  the  mucous  membranes  of  the  alimentary 
tract  were  very  little  penetrable.  Later,  Cloetta  had  a  dog  which 
in  two  years  had  become  habituated  to  a  daily  dose  of  2.6  grams 
of  arsenic  trioxide  by  mouth.  He  found  that  all  of  this  but  0.13 
per  cent.,  i.  e.,  about  -^  grain  (0.003  g111-)  a  day,  passed  out 
with  the  feces.  On  administering  hypodermatically  one-six- 
tieth the  usual  daily  amount  the  dog  died  in  six  hours.  This 
showed  that  the  mucous  membrane  of  the  alimentary  tract  had 
become  resistant  to  absorption.  Jcachimoglu  (1916)  thinks  this 
due  to  an  acquired  resistance  of  the  mucous  membrane  to  injury 
by  the  arsenic.  Cushny  states,  however,  that  in  the  arsenic- 
eaters  a  large  amount  of  arsenic  is  found  in  the  urine.  A  search 
for  antibodies  in  these  eaters  has  proved  negative  and  there  is 
no  true  immunity  conferred.  Christison  was  of  the  opinion  that 
habit  tended  to  increase  the  activity  of  the  inorganic  poisons  in 
the  blood  rather  than  to  diminish  it. 

Toxicology. — The  arsenows  compounds  are  about  twice  as 
toxic  as  the  arsemc.  Acute  poisoning  is  generally  due  to  Paris- 
green  (aceto-arsenite  fcf  copper),  or  white  arsenic,  taken  with 
suicidal  intent.  The  symptoms  come  on  slowly.  There  is  the 
gradual  onset,  in  fifteen  minutes  to  half  an  hour,  of  burning  in 
the  esophagus,  pain  in  the  abdomen,  nausea,  vomiting,  and 
cramps,  followed  by  violent  diarrhea  with  rice-water  or  bloody 
stools,  excessive  thirst,  suppression  of  the  urine,  prostration,  and 
low  blood-pressure  from  great  transudation  of  serum.  The  rice- 
water  stools  are  composed  of  serum  containing  rolled-up  flakes 
of  mucus  and  epithelial  debris. 

In  fatal  cases  the  patient  either — (i)  Grows  rapidly  weaker 
and  dies  in  from  six  to  twenty-four  hours,  or  (2)  after  partial 
recovery  from  the  acute  symptoms  passes  slowly  into  a  condition 
of  collapse,  with  death  in  a  few  days.  In  the  latter  case  the  skin 
is  said  to  exhale  an  odor  of  garlic  (arseniuretted  hydrogen) .  At 
postmortem  there  is  fatty  degeneration  of  liver,  kidneys,  heart, 
etc.,  as  mentioned  above,  and  the  poison  is  found  in  nuclein 
combination,  chiefly  in  the  liver,  but  also  in  the  other  organs 
subject  to  degeneration,  viz.,  kidneys,  spleen,  lungs,  nervous 
system,  blood,  and  the  walls  of  the  stomach  and  intestines. 
In  experimental  animals  Dutcher  and  Steel  found  the  most 
arsenic  in  muscle,  liver,  and  kidney.  Oliver  reports  that  his 


ARSENIC  (ARSENUM)  547 

dog  on  i  grain  of  arsenic  a  day  eventually  died  from  chronic 
poisoning,  but  that  no  arsenic  was  found  in  his  liver  or  bones. 

After  acute  poisoning,  recovery  from  the  acute  symptoms  may 
be  followed  by  the  manifestations  of  chronic  arsenic  poisoning. 
In  experimental  work  arsenous  acid  is  given  to  produce  acute 
vascular  nephritis,  through  its  effect  upon  the  capillaries  of  the 
glomeruli.  Nephritis  may  occur  in  acute  or  subacute  poisoning 
in  man.  (See  Kidneys  and  Suprarenals  above.) 

The  treatment  is  thorough  lavage  of  the  stomach,  bearing 
in  mind  that  the  insoluble  arsenic  preparations  may  cling 
closely  to  the  inflamed  stomach  wall  and  corrode  it,  and 
so  be  washed  off  with  difficulty.  Freshly  prepared  ferric 
hydroxide,  as  in  the  U.  S.  P.  preparation  "ferri  hydroxidum 
cum  magnesii  oxido,"  is  the  chemic  antidote.  It  oxidizes  the 
arsenows  to  an  arsem'c  compound,  and  forms  the  iron  arsena/c. 
(See  Iron.)  This  is  not  only  not  readily  absorbable,  but  when 
absorbed  is  less  readily  ionized,  and  is  therefore  less  poisonous. 
It  must  be  removed  by  lavage.  The  treatment  of  the  bowels 
presents  difficulties,  for  if  measures  are  taken  to  check  the 
diarrhea,  some  of  the  arsenic  may  be  retained  in  the  bowel  and 
absorbed.  Probably  a  large  dose  of  a  saline  cathartic,  followed, 
after  its  elimination,  by  large  doses  of  bismuth  subnitrate  and 
mucilaginous  drinks  or  olive  oil,  will  be  best  both  for  stomach  and 
bowels.  A  hot-water  bottle  or  atropine  may  relieve  the  abdomi- 
nal cramps.  Opium,  bismuth,  and  chalk  mixture  may  be  em- 
ployed, if  deemed  necessary,  for  the  diarrhea,  but  they  must  not 
be  used  too  early.  Large  doses  of  sodium  bicarbonate  are  said 
to  lessen  the  tendency  to  fatty  degeneration.  Further  treatment 
is  that  for  collapse,  bearing  in  mind  that  the  primary  collapse 
is  largely  due  to  loss  of  fluid  from  the  blood.  A  saline  infusion 
may  be  of  value,  but  transfusion  promises  better. 

Chronic  or  cumulative  arsenic  poisoning  may  be  produced  from 
the  gradual  absorption  of  very  minute  quantities,  as  from  the  dyes 
in  stockings  and  the  coloring-matter  of  wall-paper,  carpets,  cur- 
tains, artificial  flowers,  etc.  Morse  reports  poisoning  in  an  infant 
from  the  blue  silk  lining  of  its  basket.  The  famous  epidemic  of 
1900,  in  which  over  3000  cases  of  poisoning  were  discovered  in  Eng- 
land and  Wales,  occurred  from  minute  quantities  (i  to  f  of  a  grain 
of  arsenic  trioxide  per  gallon)  in  a  cheap  beer.  The  arsenic  was 
traced  back  to  the  sulphuric  acid  which  was  used  in  the  manu- 
facture of  the  glucose  employed  in  the  preparation  of  this  par- 
ticular brand  of  beer.  Starr  reports  that  of  42  samples  of  furs 
examined  in  New  York,  n  were  heavily  loaded  with  arsenic. 
Cases  of  poisoning  are  reported  from  the  therapeutic  use  of  the 
drug  in  chorea,  pernicious  anemia,  etc. 


548  PHARMACOLOGY   AND   THERAPEUTICS 

The  onset  may  be  very  insidious,  and  the  stomach  and  bowel 
symptoms,  though  regularly  present,  may  not  be  of  startling 
character.  The  patients  look  chronically  ill,  and  have  loss  of 
appetite,  nausea,  diarrhea  or  constipation,  abdominal  cramps, 
puffiness  under  the  eyes,  anemia,  headache,  irritability  of  tem- 
per, insomnia,  debility,  and  emaciation.  In  addition  there  may 
be:  (i)  Swelling  of  the  liver  with  or  without  jaundice,  associated 
with  fatty  degeneration,  and  rarely  followed  by  atrophy.  (2) 
General  edema.  (3)  Various  skin  eruptions.  (4)  A  dark  pig- 
mentation of  the  skin,  known  as  arsenic  melanosis,  with  kera- 
tosis  of  palms  and  soles,  falling  of  the  hair  and  nails,  and  other 
trophic  manifestations.  (5)  Peripheral  neuritis,  with  paralysis 
or  ataxia,  pain,  etc.,  resembling  that  from  alcohol.  (6)  Cold  in 
the  head  and  hoarse  voice. 

From  the  arsenic  treatment  of  chorea,  G.  M.  Swift  has  seen 
the  following:  hemorrhage  from  stomach,  hemorrhage  from  kid- 
neys, conjunctivitis,  neuritis,  serious  anemia,  and  tedious  gastro- 
intestinal inflammation  with  albumin  in  the  urine.  Similar  re- 
ports have  come  from  others  from  the  use  of  arsenic  in  chorea, 
pernicious  anemia,  etc.  Oliver  reports  brown  pigmentation  in 
children  treated  for  chorea.  Heffter  asserts  that  in  cases  of 
chronic  poisoning  arsenic  is  always  to  be  found  in  the  hair. 

Death  has  occurred  from  i  grain  of  arsenic  trioxide  (Kun- 
kel)  and  from  \  ounce  of  Fowler's  solution  administered  in  a 
period  of  four  days  (Taylor). 

In  the  medicinal  use  of  arsenic,  the  first  indications  of  cumu- 
lative poisoning  are  usually  puffiness  under  the  eyes,  nausea, 
diarrhea,  abdominal  cramps,  headache,  and  coryza. 

The  treatment  of  chronic  poisoning  is  stoppage  of  the  drug 
or  removal  of  the  patient  from  the  arsenic-bearing  substances, 
and  attention  to  the  general  health.  Potassium  iodide  is 
often  given,  but  Oliver  says  that  iodide  increases  the  pigmenta- 
tion of  the  skin,  and  does  not  promote  the  elimination  of  the 
drug. 

Therapeutics. — Locally. — Arsenic  trioxide  is  employed  in  the 
form  of  a  paste  as  a  caustic  for  lupus  and  superficial  epithe- 
liomata;  it  is  very  slow  in  action  and  very  painful.  It  is  used  by 
dentists  to  destroy  the  nerves  of  teeth  by  setting  up  in  them  an 
inflammatory  reaction. 

Internally,  arsenic  preparations  are  used:  (i)  In  diseases  of 
the  blood  or  blood-making  organs,  as  chlorosis,  pernicious 
anemia,  leukemia,  Hodgkin's  disease,  chronic  malaria.  (2)  In 
certain  bone  and  joint  diseases  of  obscure  origin,  as  chronic 
rheumatism,  rheumatoid  arthritis,  osteitis  deformans,  osteo- 
malacia,  and  rickets.  (3)  In  nervous  conditions,  as  chorea, 


ARSENIC  (ARSENUM)  549 

hay-fever,  and  spasmodic  asthma.  Swift  says  it  does  more  harm 
than  good  in  chorea.  (4)  In  chronic  non-parasitic  skin  diseases 
(not  in  acute  inflammatory  skin  diseases).  (5)  In  any  run-down 
conditions  with  anemia  and  poor  nutrition.  Von  Noorden  and 
others  have  found  arsenic  preparations  useless  in  diabetes, 
though  Salkowski  reported  that  in  animals  poisoned  by  arsenic 
no  artificial  diabetes  could  be  produced  by  puncture  of  the 
fourth  ventricle  or  by  curare.  Arkin  and  Korper  (1916)  state 
that  arsenic  has  no  specific  action  in  tuberculosis. 

The  organic  preparations  have  been  employed  in  trypano- 
somiasis,  Vincent's  angina,  relapsing  fever,  syphilis,  leprosy, 
pellagra,  malaria,  splenic  anemia,  leukemia,  etc.,  with  varying 
results.  It  is  claimed  that  arseno-phenyl-glycin  is  the  best 
in  trypanosomiasis  (Wendelstadt,  Roehl).  Atoxyl  has  a  very 
strong  tendency  to  produce  optic  nerve  atrophy  and  permanent 
blindness. 

Administration. — Arsenic  tri oxide  is  generally  used  with  iron 
or  strychnine  in  pills  or  as  an  elixir.  Fowler's  solution  is  mostly 
employed  by  itself  in  doses  by  drops,  one  drop  from  a  bottle  lip 
or  standard  dropper  being  practically  one  minim.  Through  some 
fallacy  it  has  become  customary  to  begin  with  a  small  dose,  say 
three  drops  three  times  a  day,  and  to  increase  the  dose  each  day 
by  a  drop  or  t\vo  until  the  patient  shows  the  first  signs  of  cumu- 
lative poisoning.  But  the  harmful  metabolic  effects  of  the  drug 
contraindicate  such  a  method  of  administration;  and  there  are 
numerous  instances  of  neuritis  and  other  toxic  manifestations 
which  bear  witness  to  the  inadvisability  of  giving  this  drug  to  its 
physiologic  limit. 

Salvarsan  and  Neosalvarsan. — In  syphilis  these  are  the 
remedies  of  choice,  the  dose  being  regularly  followed  by  a  prompt 
subsidence  of  any  acute  manifestations  of  the  disease.  Yet 
in  most  cases  they  are  not  completely  curative  and  must  be 
alternated  or  combined  with  the  mercury  treatment.  Not  only 
do  they  act  in  the  primary  and  secondary  stages,  but  according 
to  Fordyce  "in  all  the  active  manifestations  of  late  syphilis  the 
therapeutic  effect  is  almost  as  intense  as  in  the  early  contagious 
period."  Xeosalvarsan  is  more  easily  administered  and  less 
irritating  to  the  veins,  but  it  is  less  efficient  than  salvarsan. 
Fox  states  that  while  the  symptomatic  value  of  neosalvarsan  is 
only  slightly  less  than  that  of  salvarsan,  its  total  value,  estimated 
serologically,  is  considerably  less.  Adler  has  shown  that  after 
intravenous  doses  of  salvarsan,  arsenic  is  present  in  the  blood 
usually  for  thirty-six  to  forty-eight  hours  and  occasionally  for 
many  days,  and  Stiihmer's  experiments  demonstrate  that  the 
greater  part  of  the  salvarsan  becomes  stored  in  lungs,  liver,  and 


550  PHARMACOLOGY   AND   THERAPEUTICS 

spleen,  and  that  from  these  depots  it  is  doled  out  again  to  the 
blood.     The  arsenic  is  excreted  by  the  kidneys  and  intestines. 

These  drugs  are  regularly  administered  intravenously,  the 
dose  of  neosalvarsan  being  one  and  one-half  times  that  of  salvar- 
san.  The  subcutaneous  and  intramuscular  routes  have  prac- 
tically been  abandoned  for  salvarsan  because  of  its  destructive 
action  on  the  tissues;  but  for  neosalvarsan  they  are  still  employed, 
and  there  are  a  number  of  reports  from  army  surgeons  in  Europe 
of  excellent  immediate  therapeutic  effects  thus  obtained. 

In  cerebrospinal  syphilis,  and  to  a  less  extent  in  locomotor 
ataxia  and  general  paresis,  additional  clinical  improvement  has 
followed  the  intraspinous  use  of  salvarsanized  serum.  This 
method,  introduced  by  Robertson  of  Edinburgh,  has  been  brought 
into  general  clinical  use  by  Swift,  Ellis,  and  Draper.  These 
investigators  all  now  advocate  fortifying  by  a  minute  amount  of 
added  salvarsan.  The  method  given  by  Draper  is  as  follows: 
At  weekly  intervals  0.3-0.6  gm.  of  salvarsan  is  given  intra- 
venously, and  followed  forty  minutes  later  by  the  withdrawal  of 
about  50  c.c.  of  blood.  This  is  centrifuged,  and  the  serum  after 
heating  at  56°  C.  for  thirty  minutes  is  introduced  into  the  spinal 
canal  the  same  day.  The  dose  is  20  to  25  c.c.  of  100  per  cent, 
serum  or  30  c.c.  of  50  per  cent,  serum.  Salvarsan  up  to  0.0005 
gm.  maybe  added  in  vitro  before  the  injection,  or  may  be  added 
to  serum  obtained  from  blood  withdrawn  before  the  intravenous 
administration  of  the  drug.  Though  several  authors  have  claimed 
that  quite  as  much  arsenic  reaches  the  spinal  canal  after  simple 
intravenous  administration,  the  researches  of  Camp,  Hall,  and 
others  would  suggest  that  this  is  not  the  case.  In  17  cases  Camp 
administered  0.6  gm.  of  salvarsan  intravenously,  and  on  testing 
the  spinal  fluid  fifteen  minutes  to  forty  hours  later  found  arsenic 
present  in  only  one  case.  Hall  at  twenty-four  hours  found 
arsenic  present  in  the  spinal  fluid  in  2  cases  and  absent  in  4,  and 
after  neosalvarsan  found  arsenic  absent  at  one  and  a  half,  six, 
and  twenty-four  hours.  On  the  other  hand,  it  is  to  be  noted  that 
the  arsenic  readily  disappears  from  the  spinal  fluid,  for  after 
intraspinal  injections  of  3  mg.  of  neosalvarsan  in  simple  solution 
only  4  out  of  7  spinal  fluids  showed  arsenic  at  ten  hours,  and  only 
i  out  of  10  at  twenty-four  hours  (Hall).  The  method  of  adminis- 
tering neosalvarsan  intraspinally  in  simple  solution  mixed  with 
cerebrospinal  fluid  is  not  approved,  as  it  has  been  the  cause  of 
a  number  of  deaths  and  of  paralysis  of  the  lower  limbs,  probably 
because  the  amount  employed  has  been  too  large  or  the  dilution 
insufficient. 

Untoward  Effects. — i.  Locally,  there  may  be  a  cellulitis  from 
leakage  of  the  drug  into  the  tissues,  or  phlebitis  and  thrombosis  of 


ARSENIC  (ARSENUM)  551 

the  vein.  2.  From  the  intravenous  use,  the  immediate  effects,  those 
that  occur  during  or  within  a  few  minutes  of  the  injection,  are  of 
anaphylactic  nature  and  do  not  occur  at  the  first  injection.  They 
are  a  choking  feeling  or  oppression  about  the  chest  with  slight 
dyspnea,  fulness  in  the  head,  flushing  of  the  face,  cyanosis  and 
restlessness,  followed  sometimes  an  hour  or  more  later  by  a  chill, 
with  fever  and  vomiting,  and  an  urticarial  rash  or  a  generalized 
erythema.  Occasionally  during  the  injection  there  is  a  severe 
pain  in  the  lumbar  region.  Draper  reports  anaphylaxis  in  55 
per  cent,  of  all  cases,  and  always  with  the  later  doses.  His 
theory  is  that  the  drug  with  the  patient's  serum  forms  a  new 
protein  to  which  the  patient  is  sensitized  by  the  first  dose. 

The  late  effects,  those  which  occur  after  twenty-four  hours, 
are:  a  feeling  of  weight  in  the  stomach,  nausea,  vomiting  and 
diarrhea,  with  fever,  headache,  restlessness,  and  insomnia. 
Rarely  there  may  be  a  severe  illness  with  rapid,  weak  pulse,  fe- 
ver, jaundice,  urobilinuria,  albuminuria,  suppression  of  the  urine, 
or  an  arsenical  neuritis.  In  kidney  cases  uremia  has  resulted. 
Fuchs  reports  a  seven-day  heart-block.  A  number  of  deaths 
have  been  reported,  almost  all  being  due  to  collapse  in  heart 
cases,  or  to  nephritis,  hemorrhagic  encephalitis,  or  myelitis. 
Severe  symptoms  have  been  overcome  by  an  intensive  alkali- 
water  therapy  (Woodyat,  Eberly). 

The  Jarisch-Herxheimer  reaction  is  an  intensification  of  the 
symptoms  or  the  rash,  presumably  from  a  liberation  of  a  large 
amount  of  the  spirochetal  endotoxins. 

3.  From  the  intraspinal  use  numbness  of  the  feet,  severe 
pains  in  the  legs,  temporary  paraplegia,  and  severe  headache  are 
not  uncommon;  hemiplegia  and  paralysis  of  the  arms  have  also 
been  reported. 

Contraindications  and  Cautions. — The  contraindications  are: 
Severe  disease  of  the  gastro-intestinal  tract,  kidneys,  heart,  and 
arteries  not  due  to  syphilis,  any  acute  febrile  disease,  even  a  severe 
cold  in  the  head,  hemorrhage  as  after  abortion,  chronic  alcoholism, 
and  lead-poisoning.  Yak ym off  found  the  toxicity  in  mice 
increased  threefold  if  they  were  given  a  preliminary  minute 
infection  with  the  colon  bacillus.  In  some  cases  salvarsan  shows 
a  selective  action  on  the  optic  nerve,  or  on  the  auditory  nerve, 
causing  vestibular  disturbance,  so  in  diseases  of  the  eye  and  ear 
it  must  be  used  with  judgment,  as  it  has  in  many  instances 
caused  a  permanent  blindness  or  deafness. 

In  syphilitic  myocarditis  or  aortitis  the  beginning  close  should 
be  probably  not  over  0.15  gm.,  as  fatalities  have  occurred  after 
full  dosage.  Wechselmann  finds  its  use  immediately  following 
intensive  mercury  treatment  especially  dangerous  to  the  kidneys, 


552  PHARMACOLOGY   AND   THERAPEUTICS 

but  Fordyce  says  this  is  not  the  experience  of  most  observers. 
In  any  case  it  should  not  be  administered  at  less  than  five-day 
intervals.  In  infants  the  drug  must  be  used  with  caution,  as  the 
liberated  endotoxins  may  produce  disastrous  effects. 

Use  in  Non-syphilitic  Cases. — Salvarsan  has  been  employed 
for  intensive  arsenic  treatment  in  pernicious  anemia,  leukemia, 
Banti's  disease,  splenic  anemia,  and  kala-azar.  It  has  also  been 
employed  in  relapsing  fever,  frambesia,  leprosy,  amebic  dysentery, 
refractory  malaria,  filariasis,  trichiniasis,  and  many  other  condi- 
tions, with  some  good  results  and  many  failures.  The  author 
and  others  have  obtained  apparent  cures  of  chyluric  filariasis. 
It  has  been  reported  a  cure  in  experimental  trypanosomiasis. 

ANTIMONY 

The  only  official  salt  is  the  double  tartrate  of  antimony 
and  potassium,  or  tartar  emetic,  K(SbO).C4H4O6.  It  is  soluble 
in  12  parts  of  water  and  insoluble  in  alcohol. 

Preparations  and  Doses. — Antimony  and  potassium  tartrate. 
Dose,  TV  grain  (0.006  gm.).  This  enters  into: 

Compound  syrup  of  squill,  or  Coxe's  hive  syrup,  0.2  per  cent., 
with  senega  and  squill.  Dose,  30  minims  (2  c.c.). 

Compound  licorice  mixture,  0.024  Per  cent.  Dose,  i  dram 
(4  c.c.),  and 

The  unofficial  wine  of  antimony,  0.4  per  cent.  Dose,  15  min- 
ims (i  c.c.). 

Pharmacologic  Action. — Locally  it  is  irritant  and  was  for- 
merly used  as  a  pustulant. 

Systemically  it  resembles  arsenic,  but  is  absorbed  with 
greater  difficulty  and  has  a  nauseant  effect,  as  a  consequence 
of  which  it  tends  to  fluidify  and  promote  the  flow  of  mucus  in 
the  respiratory  tract.  It  was  formerly  employed  in  dose  of 
|  to  2  grains  (0.03-0.12  gm.)  as  an  emetic,  but  its  chief  use  now 
is  in  colds  in  which  the  respiratory  mucus  is  thick  and  tenacious. 

It  has  recently  been  extensively  employed  intravenously 
in  trypanosomiasis  (internal  and  external),  Leishmaniosis, 
oriental  sore,  and  kala-azar  with  specific  effect.  To  prevent 
hemolysis  Caronia  advises  solutions  of  not  over  i  per  cent, 
with  normal  saline.  The  dose  is  f  grain  (0.04  gm.)  increased  to 
3  grains  (0.2  gm.),  and  administered  at  intervals  of  two  or  three 
days.  Rogers  (1917)  recommends  the  same  treatment  in  per- 
sistent malaria.  It  maybe  given  by  mouth  in  the  form  of  anti- 
mony lithium  tartrate  in  dose-  of  TO  to  2  grains  (0.1-0.13  gm.) 
in  3  pints  (1500  c.c.)  of  water  daily  (Camac). 

Chronic  poisoning  has  been  observed  in  typesetters,  and  is 


PHOSPHORUS  553 

usually  mistaken  for  plumbism.  The  symptoms  are:  anemia, 
poor  nutrition,  constipation,  ready  fatigue,  nervousness,  in- 
somnia, dizziness,  headache,  and  pain  in  the  muscles  or  nerves. 
The  blood-pressure  tends  to  be  low,  and  the  blood  to  show  di- 
minished leukocytes  and  eosinophilia.  The  antimony  may  be 
found  in  the  stools.  The  treatment  is  the  same  as  that  for 
chronic  lead-poisoning. 

The  Hygienic  Laboratory  has  called  attention  to  the  presence 
of  antimony  in  certain  rubber  nipples  for  babies,  and  E.  W. 
Miller  (1916)  found  that  foods  took  up  antimony  from  cheap 
enamelware.  For  example,  fresh  milk  dissolved  out  3  mg.,  a 
helping  of  spinach,  10  mg.,  and  cranberry,  cider,  and  grape-juice, 
3  to  14  mg. 

PHOSPHORUS 

Phosphorus  is  insoluble  in  water,  but  soluble  in  ether,  chloro- 
form, and  the  oils.  It  is  readily  oxidized  to  phosphorous  acid, 
which  is  an  inert  compound.  It  resembles  arsenic  in  its  action, 
but  is  less  irritant  locally,  and  has  a  greater  tendency  to  produce 
fatty  degenerations.  Charteris  (1903),  in  his  studies  on  the 
bone-marrow,  administered  it  subcutaneously  to  rabbits.  In 
the  early  stages  the  marrow  showed  hyperemia  and  an  increase  in 
the  leukoblastic  tissue ;  after  prolonged  administration  the  marrow 
was  markedly  degenerated.  In  growing  animals  the  growth  of 
bone  has  been  decidedly  promoted,  the  cancellous  portion  giving 
way  to  the  development  of  hard  bone.  In  adult  animals  Char- 
teris found  no  change  in  the  bones. 

Toxicology. — Acute  poisoning  somewhat  resembles  that  from 
arsenic.  After  a  latent  period,  which  may  be  several  hours, 
there  are  burning  in  the  stomach,  abdominal  pain,  and  vomiting. 
At  first  the  liver  is  swollen,  but  it  soon  undergoes  a  rapid  atrophy 
of  the  type  of  acute  yellow  atrophy.  Jaundice  usually  comes  on 
in  twenty-four  hours.  There  are  leucin,  tyrosin,  and  other 
incompletely  oxidized  bodies  in  the  urine.  The  local  antidote 
is  an  oxidizing  agent,  such  as  peroxide  of  hydrogen  or  potassium 
permanganate.  Scoville  says  that  old  turpentine  oil  changes  the 
phosphorus  into  a  non- toxic  turpentine-phosphorous  acid.  Other 
oils  should  not  be  employed  unless  promptly  washed  from  the 
stomach. 

Chronic  poisoning  is  to  be  seen  among  the  makers  of  matches, 
Its  chief  manifestation  is  "fossy  jaw,"  a  condition  of  necrosis 
of  the  jaw  bones  which  is  incurable,  and  often  necessitates 
extensive  curetage  of  the  parts  to  check  the  horrible  cadaverous 
odor.  It  may  even  require  removal  of  the  entire  maxilla.  Char- 
teris laid  bare  the  periosteum  of  the  lower  jaw  of  rabbits,  and 


554  PHARMACOLOGY   AND   THERAPEUTICS 

repeatedly  exposed  them  to  phosphorus  fumes,  but  could  not 
get  necrosis. 

Therapeutics. — Phosphorus  has  been  used  in  dose  of  y^ 
grain  (0.0006  gm.)  in  the  treatment  of  rickets  and  osteomalacia. 
It  is  given  in  the  form  of  a  pill,  an  elixir,  or  a  i  per  cent,  solution 
in  olive  oil.  It  is  probably  mostly  inert. 

Tlie  hypo  phosphites  (Na2P02,  CaPO2,  etc.)  have  been  much 
employed  as  nerve  tonics.  The  belief  that  they  furnish  phos- 
phorus to  the  nerve  tissues  is  negatived  by  the  fact  that  they  pass 
unchanged  through  the  system,  and  can  be  almost  entirely 
recovered  from  the  urine  as  hypophosphites.  The  compound 
syrup  of  the  hypophosphites  contains  the  hypophosphites  of  cal- 
cium, potassium,  and  sodium;  dose,  2  drams  (8  c.c.). 

The  Glycero phosphates. — Calcium  glycerophosphate,  CaPO4.- 
C3H5(OH)2,  is  soluble  in  50  parts  of  water  at  25°  F.  ( — 4°  C.)  and 
more  soluble  at  lower  temperatures;  the  sodium  salt,  Na2PO4.- 
C3H5(OH)2,  is  very  soluble  in  water  and  is  deliquescent.  Dose 
of  each,  4  grains  (0.24  gm.)  They  are  esters  of  phosphoric 
acid,  and  their  administration  results  in  an  increase  in  the  urinary 
phosphates.  They  are  at  the  present  time  much  in  use  as  general 
"nerve  tonics,"  and  have  largely  replaced  the  useless  hypophos- 
phites. But  there  is  no  satisfactory  evidence  that  they  increase 
the  phosphorus  in  the  nervous  tissues,  or  that  in  exhaustion  the 
nervous  tissues  are  lacking  in  phosphorus;  and  there  is  abundant 
evidence  that  the  body  can  get  its  needed  phosphorus  quite  as 
well  from  the  inorganic  phosphates;  at  least  this  is  the  case  in 
hens  and  ducks,  which  give  out  a  large  amount  of  phosphorus 
in  their  eggs  in  the  form  of  lecithin.  Fingerling  tried  to  enrich 
the  milk  of  goats  by  the  administration  of  phosphorus  compounds. 
He  found  that,  even  when  the  food  was  deficient  in  phosphorus, 
the  organic  phosphorus  compounds  exerted  no  more  favorable 
influence  than  the  inorganic  ones.  Marshall  (1915)  corroborates 
this  finding. 

Lecithin  (see  page  32)  is  a  glycerophosphoric  acid,  substituted 
by  two  fatty  acid  radicals,  and  combined  with  choline.  It 
contains  about  4  per  cent,  of  phosphorus,  and  probably  sets  free 
phosphoric  acid.  It  occurs  in  most  animal  and  plant  cells,  but 
especially  in  the  brain  and  nerves,  yolk  of  egg,  fish-eggs,  blood- 
plasma,  and  bile.  An  ordinary  mixed  diet  may  furnish  as  much 
as  i  to  2  drams  (4-8  gm.)  per  day  (von  Noorden).  It  is  broken 
up  by  the  pancreatic  juice  into  glycerophosphoric  acid,  fatty 
acids,  and  choline  (Dixon).  When  used  in  the  emulsification  of 
fats  it  promotes  their  absorption. 

It  is  "a  very  important  material  for  building  up  the  compli- 
cated phosphorized  nuclein  substances  of  the  cell  and  cell 


THE    IODIDES  555 

nucleus"  (Hammarsten) .  Its  administration  in  large  amounts 
in  anemia  tends  to  increase  the  hemoglobin  and  red  cells  and  to 
improve  the  nutrition.  Nerking,  by  the  injection  of  a  lecithin- 
saline  solution  in  rabbits,  was  able  to  cut  short  or  abolish  anes- 
thesia and  narcosis.  He  looked  upon  this  as  evidence  in  favor 
of  the  Meyer-Overton  theory  of  narcosis. 

When  eggs  are  available  it  hardly  seems  of  advantage  to 
prescribe  the  commercial  lecithin  in  doses  of  5  to  10  grains 
(0.3-0. 7  gm.). 

THE   IODIDES 

Preparations  and  Doses. — Iodine  (iodum),  J¥  grain  (0.006 
gm.). 

Sodium  iodide,  potassium  iodide,  10  grains  (0.7  gm.);  diluted 
hydriodic  acid,  10  per  cent.,  i  dram  (4  c.c.). 

Tincture  of  iodine,  7  per  cent,  iodine  and  5  per  cent,  potas- 
sium iodide,  with  alcohol. 

Compound  solution  of  iodine  (Lugol's  solution),  an  aqueous 
solution  of  5  per  cent,  of  iodine  and  10  per  cent,  of  potassium 
iodide. 

lodoform,  CHI3,  4  grains  (0.25  gm.). 

Iodipin,  sajodin,  and  iodival  are  iodized  fats.  lodalbin  and 
iodocasein  are  iodized  albumins.  According  to  Leathes  (1911) 
iodipin  can  be  absorbed  and  stored  up  as  fat  without  giving  up 
its  iodine  to  the  tissues.  McLean  found  that  iodine  derivatives 
of  fats  and  fatty  acids  are  held  in  part  by  the  lipoids  of  the  cells. 
The  iodized  albumins  are  better  borne  by  the  stomach  than  the 
alkaline  salts,  but  have  no  other  differences  in  action.  The  dose 
of  iodipin  is  i  dram  (4  c.c.)  in  emulsion,  that  of  sajodin,  iodival, 
and  iodocasein  is  10  grains  (0.7  gm.). 

Pharmacologic  Action. — Externally. — For  the  external  action 
of  iodine  see  Counterirritants  and  Disinfectants. 

Internally. — The  alkaline  iodides  are  freely  soluble  in  water 
and  have  a  disagreeable  bitter  taste  and  a  salt  action.  Locally 
they  are  irritant,  so  require  proper  dilution  before  their  admin- 
istration. They  have  always  been  considered  valuable  remedies, 
but  their  mode  of  action  has  been  the  subject  of  much  surmise, 
It  is  generally  understood  that  they  promote  the  flow  of  saliva 
and  respiratory  mucus,  that  they  increase  the  activity  of  the 
thyroid  gland,  and  that  they  tend  to  lessen  the  viscosity  of  the 
blood.  Mueller  and  Inada  hold  that  the  viscosity  is  lessened, 
but  Determunn  says  not.  Adam  thought  that  ordinary  doses 
were  too  small  to  cause  decreased  viscosity,  though  large  amounts 
would  do  so.  Jorns  and  also  Boveri  find  that  small  doses  for 
long  periods  lessen  the  viscosity. 


556  PHARMACOLOGY  AND  THERAPEUTICS 

Absorption  and  excretion  are  rapid,  iodine  being  recoverable 
from  the  saliva  and  urine  a  few  minutes  after  their  ingestion. 
Hanzlik  (1912)  found  that  with  sodium  iodide  in  i  to  10  per 
cent,  solution  there  was  a  rapid  initial  absorption  of  50  to  75 
per  cent,  of  the  total,  and  then  a  marked  inhibition  of  absorp- 
tion due  to  a  local  effect  on  the  absorbing  epithelium.  He  found 
also  that  the  application  to  the  mucous  membrane  of  0.2  to 
i  per  cent,  sodium  chloride  prevented  absorption  of  the  iodide. 

Unlike  many  salts,  they  do  not  remain  in  the  body,  but  are 
excreted  rapidly  by  the  kidneys.  Seventy-five  per  cent,  of 
the  dose  appears  in  the  urine  inside  of  twenty-four  hours.  The 
remainder  may  remain  in  organic  combination  in  the  body. 
In  fatty  combination  they  are  held  by  the  lipoids  of  the  cells  for 
a  longer  time.  The  excretion  is  much  retarded  in  chronic  passive 
congestion  of  the  kidneys  and  interstitial  nephritis.  Iodine 
is  not  found  in  the  cerebrospinal  fluid,  even  after  very  large  doses 
by  mouth. 

Because  of  its  excretion  in  the  saliva,  it  may  produce  a  very 
unpleasant  metallic  taste  in  the  mouth,  with  coated  tongue. 
To  avoid  this  it  is  recommended  to  gargle  with  a  solution  of 
sodium  bicarbonate  during  the  iodide  administration. 

Action  on  the  Thyroid  Gland. — (See  next  article  on  Thyroid 
Gland.) 

Marine  and  Lenhart  (1909)  found  that  iodine  given  in  any 
form  was  taken  up  by  the  thyroids,  whether  these  were  normal, 
colloid,  or  hyperplastic ;  that  the  subjects  with  hyperplastic 
glands  lost  weight  for  one  or  two  weeks,  then  rapidly  gained; 
and  that  iodine  hastened  the  tendency  of  all  active  hyperplasias 
to  revert  to  colloid. 

Many  of  the  experiments  have  suggested  that  much  of  the 
benefit  of  iodides  in  a  number  of  conditions  may  be  due  to  in- 
creased thyroid  activity. 

Circulation. — In  normal  persons  or  laboratory  animals  iodides 
have  no  measurable  effect  upon  the  blood-pressure,  but  in  those 
with  high  arterial  tension  they  have  a  tendency  to  lower  it. 
This  effect  is  probably  due  both  to  the  lessening  of  the  viscosity 
of  the  blood  and  to  the  increase  in  thyroid  activity.  Their  value 
in  arteriosclerosis  may  possibly  be  due  to  improved  blood-flow 
in  the  va^a  vasorum,  owing  to  diminished  viscosity  of  the  blood. 
From  sodium  iodide  Macht  found  a  stimulating  effect  on  the 
heart  and  arteries,  and  from  potassium  iodide  a  depressing  effect. 

Respiratory  Organs. — There  is  increased  fluidity  of  mucus 
in  the  nose,  throat,  and  bronchi.  This  is  considered  by  Hender- 
son and  Taylor  (1910)  to  be  a  reflex  effect.  In  tuberculosis, 
iodides  are  believed  to  be  harmful,  because  of  their  tendency 


THE   IODIDES  557 

to  interfere  with  connective-tissue  formation  and  to  soften  the 
caseous  matter;  for  this  promotes  the  spread  of  the  disease.  In 
cases  with  doubtful  physical  signs  of  tuberculosis  it  is  a  common 
custom  to  administer  iodides  to  "bring  out  the  rales."  But  the 
author's  clinical  experience  coincides  with  that  of  others  in 
finding  this  a  dangerous  practice,  and  the  experiments  of  Sorel 
(1909)  give  additional  proof  that  tuberculosis  is  a  contra- 
indication to  iodide.  Sorel  infected  guinea-pigs  with  the  tubercle 
bacillus,  then  administered  potassium  iodide  to  a  certain  number 
of  them.  The  iodide  pigs  died  of  tuberculosis  some  weeks 
earlier  on  the  average  than  those  which  did  not  get  the  iodide. 
It  has  been  reported  also  that  weak  doses  of  iodide  in  the  tuber- 
culous will  give  a  reaction  similar  to  that  of  fair  doses  of  tuber- 
culin, a  reaction  which  may  help  to  establish  a  diagnosis,  but  is 
not  without  danger.  Iodide  is  said  also  to  give  such  a  reaction 
in  lepers.  A  positive  luetin  reaction  can  be  obtained  in  those 
taking  iodide. 

In  asthma  associated  with  chronic  bronchitis  and  emphysema 
the  action  of  iodides  is  probably  an  expectorant  one. 

Theory  of  Action  in  Syphilis  and  Tuberculosis. — Necrotic 
tissues  in  syphilis  (gumma)  and  tuberculosis  (caseous  areas)  take 
up  more  iodine  than  other  tissues,  and  Jobling  and  Petersen  find 
that  both  in  the  blood  and  the  necrotic  material  iodine  combines 
with  and  renders  inert  the  antitrypsin  which  is  the  normal  pre- 
ventive of  the  resolution  of  necrotic  tissue.  As  a  result  the 
caseous  matter  is  subjected  to  attacks  by  the  tryptic  ferments 
and  is  digested  and  absorbed,  the  contained  bacteria  being  set 
free.  In  the  case  of  syphilis  iodides  are  valuable  because  the 
gummata  are  absorbed  and  the  contained  bacteria  are  rendered 
accessible  to  germicidal  agents  such  as  mercury  or  salvarsan. 
In  the  case  of  tuberculosis  of  the  lungs  iodides  are  prone  to  be 
harmful,  for  as  the  cheesy  matter  is  absorbed  tubercle  bacilli  are 
set  free  and  may  spread  the  infection  or  be  expectorated;  further- 
more, arteries  in  the  caseous  areas,  having  lost  their  support, 
may  rupture  and  cause  hemorrhage. 

Untoward  Actions. — Besides  the  local  irritation  of  the  stom- 
ach, the  most  frequent  undesirable  effects  are  those  upon  the  skin 
and  mucous  membranes. 

i.  Skin. — The  skin  lesion  usually  shows  as  irregularly  scat- 
tered pimples,  the  chief  sites  of  which  are  the  face,  shoulders, 
neck,  and  back.  It  has  been  thought  that  the  skin  affection 
was  due  to  elimination  of  the  drug  by  the  sebaceous  glands,  and 
its  decomposition  by  the  fatty  acids  of  the  sebaceous  secretion. 
But  many  investigators  have  failed  to  find  either  free  iodine 
or  iodide  in  the  sebaceous  secretion,  and  the  dermatopathologists 


558  PHARMACOLOGY   AND   THERAPEUTICS 

agree  that  the  changes  begin  in  the  papillary  layer  and  not  in 
the  glands  (Stelvvagon) . 

Other  skin  lesions  than  acne  may  make  their  appearance, 
as  urticaria  or  a  vesicular  or  bullous  or  hemorrhagic-bullous  or 
purpuric  eruption,  or  disseminated,  bright  or  dusky  red,  and 
painful  nodules.  A  few  cases  of  carbuncle  formation  with 
serious  destruction  of  the  subdermal  tissues  are  reported,  even 
resulting  in  death.  The  serious  eruptions  usually  occur  in 
patients  with  much  lowered  vitality,  and  especially  in  those  with 
chronic  nephritis. 

2.  Mucous  Membranes. — The  mucous  membranes  chiefly 
irritated  are  the  conjunctivas  and  those  of  nose,  throat,  bronchi, 
and  stomach.  A  not  unusual  effect  is  that  of  a  severe  cold  in 
the  head,  with  watery,  injected  eyes,  headache,  and  general 
malaise;  there  may  be,  in  addition,  nausea,  salivation,  and  tender 
teeth  and  gums.  The  patients  think  they  have  influenza.  A 
number  of  cases  of  edema  of  the  glottis  have  been  reported,  also 
purpuric  eruptions  on  the  mucous  membranes,  and  inflammation 
and  swelling  of  the  parotid  glands. 

It  has  been  ascertained  by  extensive  clinical  experience  that 
the  minor  eruptions  are  more  frequent  from  the  smaller  doses 
of  5  or  10  grains,  and  that  they  sometimes  disappear  when  the 
dose  is  increased. 

Prophylactic  measures  against  the  lesions  of  skin  and  mucous 
membranes  are  great  cleanliness  of  skin  and  mouth,  alkalies, 
and  arsenic.  Some  think  that  the  sodium  iodide  is  less  irritating 
than  the  other  salts. 

Iodide  Fever. — In  a  case  of  plumbism,  Oliver  reports  a  tem- 
perature of  101.8°  F.,  and  albumin  in  the  urine  from  5 -grain 
doses  of  potassium  iodide.  In  a  case  of  chronic  rheumatism 
of  the  author's  (1912)  10  grains  of  potassium  iodide  three  times 
a  day  caused  swelling  and  intense  burning  of  the  face  and  hands, 
fever,  and  eventually  delirium.  It  was  learned  that  the  same 
phenomena  had  followed  iodide  the  previous  year.  Konried 
reports  two  cases  of  iodide  fever,  one  of  them  being  from  the  local 
use  of  an  ointment.  Longcope  suggests  that  there  may  be  a 
sensitization  of  the  patient  by  the  formation  of  a  new  protein 
out  of  the  drug  and  the  patient's  serum. 

Chronic  iodism  is  a  state  in  which  there  are  anemia  and  emacia- 
tion, nervousness,  tachycardia,  and  loss  of  sexual  power.  Much 
iodide,  even  without  any  poisonous  symptoms,  tends  to  lower 
the  body  tone  and  to  depress  the  spirits. 

Therapeutics. — Iodides  are  believed  to  be  more  or  less  spe- 
cific in  tertiary  syphilis  and  actinomycosis.  They  do  not  pre- 
vent the  development  of  experimental  syphilis.  According 


Fig.  65. — Dermatitis  medicamentosa  of  pustulobullous  type,  following  inges- 
tion  of  potassium  iodide.  Principally  upon  the  face,  with  some  pustular  lesions  on 
the  neck  and  shoulders.  Subsided  upon  withdrawal  of  the  drug,  and  recurred  on 
experimental  readministration  (Stelwagon). 


Fig.  66. — Dermatitis  medicamentosa  of  a  bullous  type,  from  the  ingestion  of 
potassium  iodide  in  a  woman  aged  fifty.  Face,  neck,  forearms,  and  hands  in- 
volved, and  the  seat  of  considerable  edematous  swelling  and  variously  sized  blebs. 
In  some  parts  blebs  became  confluent,  broke,  and  uncovered  a  superficially  ex- 
coriated surface,  as  shown  in  cut.  Recovery  without  any  scarring  or  other  trace. 
Patient  had  a  weak  heart  (Stelwagon). 


THE    IODIDES  559 

to  Jonathan  Hutchinson,  "Over  the  tertiary  manifestations 
of  syphilis,  the  gumma,  whether  of  skin,  cellular  tissue,  coats 
of  arteries,  cerebral  meninges,  or  periosteum,  potassium  iodide 
exercises  almost  as  definite  an  influence  as  mercury  over  the 
earlier  ones."  Fordyce  says  that  iodide  has  no  effect  on  the 
early  lesions  of  syphilis,  and  only  a  negligible  one  in  rendering 
the  Wassermann  reaction  negative.  It  has,  however,  a  profound 
and  physiologic  effect  on  the  later  lesions. 
Iodides  are  also  employed  in: 

1 .  The  asthma  of  emphysema  and  chronic  bronchitis. 

2.  Arteriosclerosis  and  some  other  conditions  with  chronic 
connective- tissue  production;  not  in  cirrhosis  of  the  liver  or 
chronic  nephritis  (unless  for  arterial  hypertension). 

3.  Aneurysm  of  the  aorta. 

4.  Cases  with  arterial  tension,  from  whatever  cause. 

5.  Chronic  rheumatism  or  rheumatoid  affections. 

6.  Poisoning  by  the  heavy  metals.     Oliver  believes  them  of 
little  or  no  use  in  promoting  the  excretion  of  metallic  poisons, 
and  Cowers  states  that  they  increase  the  poisoning  by  promoting 
the  solubility  of  the  metal. 

7.  Colloid   goiter — Schondroff   calls   attention   to   the   good 
results  that  have  been  obtained   from   iodides  and  from  sea 
plants  containing  iodine. 

It  is  generally  thought  that  they  should  not  be  used  in  hyper- 
thyroidism.  Krehl  advises  strongly  against  their  use,  as  he  has 
seen  latent  hyperthyroidism  change  under  small  doses  of  iodide 
into  a  permanently  intractable  active  form.  But  Marine  and 
Lenhart  (1909)  point  out  that  in  the  hyperplastic  glands  small 
doses  tend  to  hasten  the  change  to  colloid,  which  may  be  desir- 
able. They  advise  very  small  doses.  There  are  a  number  of 
reports  of  the  development  of  exophthalmic  goiter  as  the  result 
of  iodine  medication. 

Contraindications. — The  chief  of  these  is  pulmonary  tuber- 
culosis. 

Administration. — Potassium  or  sodium  iodide  may  be  given 
in  milk  ("best  way  of  all" — Dock),  or  in  saturated  aqueous 
solution,  or  in  dilute  solution  flavored  with  compound  syrup 
of  sarsaparilla  or  syrup  of  orange-peel.  Of  the  saturated  solu- 
tion of  potassium  iodide  in  water,  i  minim  is  practically  a  drop, 
as  dropped  from  a  bottle  mouth  or  standard  dropper,  and  it 
contains  i  grain.  In  syphilis  this  is  often  begun  by  three  doses 
a  day  of  10  to  15  drops  (0.7-1  c.c.),  this  dose  being  increased  one 
drop  each  day  until  45  or  60  grains  (3  to  4  gm.)  of  the  drug  are 
being  taken  three  times  a  day.  For  convenience,  compressed 
tablets  may  be  employed,  but  they  should  be  dissolved  before 


560  PHARMACOLOGY   AND   THERAPEUTICS 

swallowing,  or  taken  with  a  large  draught  of  water.  Klemperer 
and  others  have  used  sodium  iodide  intravenously  in  doses  of  i| 
to  2\  drams  (5-10  grn.)  two  or  three  times  a  week. 

THYROID   GLAND 

Desiccated  thyroid  glands  (thyroideum  siccum)  are  the 
dried  thyroids  of  various  domestic  animals,  and  are  required  by 
the  Pharmacopoeia  to  contain  between  0.17  and  0.23  per  cent,  of 
iodine.  They  are  administered  in  tablet  or  capsule  form;  dose, 
i  to  5  grains  (0.06-0.3  gm.)  one  to  three  times  a  day.  The 
commercial  article  regularly  contains  iodine,  and  yields  by  special 
treatment  various  principles,  such  as  thyroiodin  and  thyreo- 
globulin.  Kendall  has  isolated  a  number  of  chemical  principles, 
each  of  which  has  a  special  physiologic  activity.  The  alpha- 
iodine  compound  most  closely  represents  thyroid  activity. 

Iodine  Content. — Most  thyroid  glands  contain  iodine.  In 
the  dried  glands  of  adult  human  beings  Vincent  found  0.3  to 
0.9  per  cent. ;  in  the  dried  glands  of  seven  dogs  Seidell  obtained 
0.036  to  0.271  per  cent.;  and  in  ten  sheep's  thyroids  dried,  Simp- 
son and  Hunter  obtained  0.048  to  0.383  per  cent.  But  in  the 
thyroids  of  many  children  and  those  of  certain  individuals  of 
various  species,  as  the  ox,  horse,  pig,  sheep,  etc.,  iodine  has  been 
present  in  mere  traces  or  totally  absent.  Yet  these  animals 
seem  to  get  along  as  well  as  those  with  iodine-containing  thyroids, 
and  cannot  be  distinguished  from  them ;  and  after  thyroidectomy 
they  show  just  as  severe  symptoms  as  those  with  even  a  high 
percentage  of  iodine  in  their  thyroids.  It  is  evident,  therefore, 
as  Vincent  says,  that  thyroid  gland  free  from  iodine  seems  to 
meet  the  needs  of  the  body  apparently  as  well  as  that  contain- 
ing iodine. 

But  the  experiments  of  Baumann,  Roos,  Hunt,  and  many 
others  point  out  the  ability  of  the  gland  to  take  iodine  given  by 
mouth  into  organic  combination,  and  Hunt  and  Seidell  have 
shown  that  there  is  a  parallelism  between  the  iodine  content  of 
thyroid  and  its  physiologic  activity.  In  their  experiments,  46 
dogs  were  used.  On  two  successive  days,  1.5  to  2  gm.  of  potas- 
sium iodide,  or  i  to  1.3  gm.  of  iodoform  (CHI3),  were  adminis- 
tered by  mouth,  and  on  the  third  day  the  dog  was  killed.  The 
thyroids  of  the  iodoform  dogs  averaged  0.3  per  cent,  of  iodine, 
and  of  the  iodide  dogs,  0.148  per  cent. ;  while  those  of  the  controls 
ranged  between  0.106  and  0.129  per  cent.  These  thyroids  were 
then  tested  on  rats  and  mice,  and  were  found  to  decrease  the 
resistance  of  rats  and  mice  to  poisoning  by  morphine  and  of 
rats  to  poisoning  by  acetonitril,  practically  in  proportion  to  the 
percentage  of  iodine  present. 


THYROID   GLAND  561 

From  the  many  experiments  with  thyroid  the  numeric  indi- 
cator of  the  activity  of  the  preparation  would  seem  to  be  the 
percentage  of  iodine.  And  this  has  led  to  the  belief,  on  the  part 
of  some  investigators,  that  commercial  thyroid  is  merely  a  special 
form  in  which  iodine  may  be  administered  in  organic  combina- 
tion. That  this  is  true  in  some  cases  is  indicated  by  the  resem- 
blance of  the  effects  to  those  of  other  iodine  preparations;  but 
in  thyroid  absence,  as  in  myxedema  or  cretinism  or  after  thy- 
roidectomy,  no  other  iodine  preparation  is  of  any  avail. 

Pharmacology. — Protein  Metabolism. — Roos  (1899)  found  that 
thyroid  rich  in  iodine  caused  a  marked  increase  in  nitrogen 
excretion;  that  thyroid  poor  in  iodine  caused  scarcely  any  in- 
crease, and  that  iodine-free  thyroid  had  no  effect  at  all  on  the 
nitrogen.  Oswald  found  the  same  to  be  true  of  thyreoglobulin, 
the  presence  or  absence  of  iodine  determining  the  increase  or 
otherwise  of  nitrogen  metabolism.  Schondroff,  after  a  series 
of  experiments  of  long  duration,  came  to  the  same  conclu- 
sion. In  4  patients  with  dementia  praecox,  Ross  noted  an  in- 
creased output  of  total  nitrogen,  creatinin,  and  indolacetic  acid. 
It  may  therefore  be  taken  as  established  that  commercial  thyroid, 
which  regularly  contains  iodine,  increases  protein  loss. 

Fat  Metabolism. — As  long  ago  as  1894  thyroid  was  recom- 
mended in  obesity.  Stuve,  in  tests  with  healthy  men,  found  the 
consumption  of  oxygen  increased  about  20  per  cent.,  and  Thiele 
and  Nehring  obtained  similar  results.  In  myxedema  Magnus- 
Levy  recorded  an  increase  of  80  per  cent.  These  figures  indicate 
a  loss  of  fat  out  of  proportion  to  the  loss  of  protein.  Marine 
and  Williams  (1908)  found  in  a  dog  that  in  eighteen  days  n  gm. 
of  dried  sheep's  thyroid  containing  0.0292  per  cent,  of  iodine 
caused  no  loss  of  weight;  while  in  another  dog,  in  the  same  time, 
ii  gm.  of  a  preparation  containing  0.1092  per  cent,  of  iodine 
caused  a  loss  in  weight  of  454  gm.  There  are  many  clinical 
reports  pointing  to  the  value  of  thyroid  in  obesity,  but  it  must 
be  remembered  that,  with  the  reduction  of  fat,  there  is  also 
excessive  protein  destruction,  and  this  is  a  serious  feature  in 
any  reduction  cure. 

Bone. — Many  surgeons  have  attested  to  the  power  of  thy- 
roid to  promote  union  in  delayed  fractures,  and  Bircher  (1910) 
has  found  that  it  promotes  the  growth  of  bone  in  normal  animals. 

Relation  to  Adrenals. — Cretins  have  large  adrenals  (Carlson), 
and  Cannon  has  shown  that  thyroid  activity  may  be,  at  least  in 
some  measure,  dependent  upon  the  epinephrine  supply.  Cannon 
has  further  shown  that  thyreoglobulin  or  stimulation  of  the  thy- 
roid gland  augments  the  activity  of  the  adrenals. 

Toxicology. — An  intravenous  dose  causes  a  slowing  of  the 
36 


562  PHARMACOLOGY   AND   THERAPEUTICS 

pulse  and  a  fall  in  blood-pressure.  As  this  is  prevented  by 
atropine  or  by  cutting  the  vagi,  it  must  be  due  to  stimulation  of 
the  vagus  center. 

When  the  drug  is  given  in  full  dosage  for  long  periods  to 
dogs,  cats,  horses,  sheep,  etc.,  and  especially  when  given  to 
monkeys  and  man,  it  produces  a  regular  group  of  effects.  There 
are  anemia,  emaciation  and  muscular  weakness,  excessive  sweat- 
ing, a  tendency  to  fever,  headache,  nervousness,  tremor  of  face 
and  limbs,  various  pains  and  tingling  or  pricking  sensations  or 
paralyses,  increased  heart-rate,  and  sometimes  exophthalmos 
and  dilatation  of  the  pupil.  Similar  effects  are  to  be  seen  in 
exophthalmic  goiter,  and  some  of  them  suggest  stimulation  of 
the  sympathetic  nervous  system.  In  monkeys  Edmunds  found 
that  death  occurred  from  asthenia. 

Therapeutics. — (i)  In  Myxedema  and  Cretinism. — In  these 
conditions  the  effects  are  most  striking.  In  myxedema  the 
mentality  and  the  physical  characteristics  are  restored;  in  cre- 
tinism the  patient  may  be  changed  from  a  maldeveloped  and 
hopelessly  idiotic  child  to  a  well-developed  and  more  intelligent 
one.  Complete  change  to  normal  is  not  obtained. 

(2)  After  Thyroidectomy — to  prevent  the  usual  train  of  symp- 
toms.    It  is  effective  if  the  parathyroids  have  not  been  removed. 

(3)  In  Hypothyroidism,  as  after  some  partial  thyroidectomies, 
and  in  the  late  stages  of  exophthalmic  goiter  where  reversion 
to  colloid  has  taken  place.     It  is  believed  that  there  are  many 
cases  of  hypothyroidism,  with  ill-dsfined  symptoms,  in  which 
thyroid  may  be  of  benefit;  but  the  distinguishing  features  of 
this  condition  have  not  been  satisfactorily  determined. 

(4)  In  Colloid  Goiter.     (5)   In  Obesity.     (6)  In  Rheumatoid 
Arthritis.     (7)    In    Infantile    Wasting.     (8)    In    Osteomalacia, 
Rickets,  and  Delayed  Union  of  Fractures. 

It  is  contraindicated  in  the  hyperplasia  stage  of  exophthalmic 
goiter,  as  it  increases  the  symptoms.  (For  recent  reviews  on 
thyroid,  see  books  on  Internal  Secretions  by  Swale  Vincent  and 
Biedl.) 

ANTITHYROID  PREPARATIONS 

There  are  several  preparations  on  the  market  designed  to 
overcome  thyroid  hyperactivity.  The  best  known  are: 

Beebe's  serum,  a  serum  obtained  from  animals  after  inocula- 
tion with  the  proteins  from  human  thyroids. 

Antithyroidin  (Moebius)  the  blood-serum  obtained  from  sheep 
whose  thyroid  glands  had  been  removed  at  least  six  weeks  before. 
It  is  preserved  with  0.5  per  cent,  of  phenol,  and  is  given  by  mouth 
in  dose  of  8  to  15  minims  (0.5-1  c.c.)  three  times  a  day. 


EXPECTORANTS  563 

Thyreoidectin,  consisting  of  gelatin  capsules  each  containing 
5  grains  (0.3  gm.)  of  a  powder  prepared  from  the  dried  blood  of 
thyroidectomized  animals.  Dose,  one  or  two  capsules  three 
times  a  day. 

Any  therapeutic  value  from  these  preparations  is  very 
doubtful. 

EXPECTORANTS 

Expectorants  are  remedies  which  facilitate  the  expulsion  of 
mucus  from  the  respiratory  organs.  They  do  this  largely  by 
increasing  the  fluidity  or  the  rate  of  the  secretion.  Most  of 
them  act  reflexly  from  an  irritant  (nauseant)  action  in  the  stom- 
ach. Henderson  and  Taylor  (1910)  believed  this  to  be  the  case 
with  ammonium  compounds,  antimony,  ipecac,  and  senega. 
Coleman  holds  that  ammonium  chloride  fluidifies  by  increasing 
the  water  in  the  bronchi,  which  it  carries  out  as  the  medium  of 
its  own  excretion  (see  Ammonium  Chloride) .  We  have  considered 
the  ammonium  salts,  iodide,  antimony,  and  pilocarpine.  Others 
in  common  use  are:  Ipecac,  i  grain  (0.06  gm.);  senega,  15  grains 
(i  gm.),  and  aspidosperma  (quebracho),  30  grains  (2  gm.).  Que- 
bracho and  its  alkaloids,  quebrachine  and  aspidospermine,  have 
a  peripheral  action  of  the  nicotine- curare  type,  and  stimulate 
the  respiratory  center,  hence  have  been  employed  in  emphysema 
and  asthma.  In  a  test-tube  the  alkalies  liquefy  mucus,  but 
when  given  by  mouth  probably  have  no  effect  in  the  bronchi. 

Certain  bronchial  antiseptics  have  been  mentioned  under 
Antiseptics.  Whether  or  not  they  act  as  true  expectorants  is 
a  question;  and  whether  they  are  eliminated  in  the  bronchial 
mucus  in  sufficient  quantity  to  stimulate  the  mucous  membrane 
or  to  act  as  antiseptics  has  not  been  proved.  They  are:  Certain 
volatile  oil  drugs,  as  oil  of  turpentine,  terebene,  pine  needle  oil, 
tar,  creosote,  camphor,  cubebs,  and  garlic,  dose,  5  minims 
(0.3  c.c.)  or  5  grains  (0.3  gm.);  also  terpin  hydrate,  dose,  5  grains 
(0.3  gm.),  benzoic  acid,  benzoin,  balsam  of  Tolu,  and  balsam  of 
Peru.  The  syrup  of  tar,  syrupus  picis  liquids,  has  a  dose  of  i 
dram  (4  c.c.). 

In  some  cases  bronchial  activity  is  promoted  by  the  tonic 
action  of  such  a  drug  as  strychnine. 

Favorite  expectorant  mixtures  are: 

i.  The  compound  licorice  mixture,  brown  mixture  (not 
Brown's  Mixture),  which  contains  extract  of  licorice  and  spirit 
of  nitrous  ether,  each  3  parts,  paregoric  12  parts,  and  antimony 
and  potassium  tartrate  0.024  part  in  100,  with  syrup,  acacia,  and 
water.  Dose,  i  dram  (4  c.c.).  It  is  not  a  very  effective  ex- 
pectorant. 


564  PHARMACOLOGY  AND  THERAPEUTICS 

2.  The  compound  syrup  of  squill  (Coxe's  hive  syrup),  which 
contains  8  parts  each  of  the  fluidextracts  of  squill  and  senega, 
and  0.2  part  of  tartar  emetic  per  100.     Dose,  \  dram  (2  c.c.) 
every  two  or  three  hours. 

3.  Mistura  pectoralis,  N.   F.    (Stokes'  mixture),  containing 
ammonium  carbonate,  8  grains  (0.5  gm.),  the  fluidextracts  of 
senega  and  squill,  each,  15  minims  (i  c.c.),  paregoric,  75  minims 
(5  c.c.)  in  each  ounce  (30  c.c.),  with  syrup  of  Tolu.     Dose,  i 
dram  (4  c.c.)  every  two  or  three  hours. 

Therapeutics. — To  promote  the  flow  of  mucus  and  lessen 
congestion  in  the  respiratory  tract,  particularly  in  the  dry  stages 
of  bronchial,  nasal,  or  laryngeal  inflammation. 

IPECACUANHA 

Ipecac  (ipecacuanha)  is  the  root  of  Cephaelis  Ipecacuanha 
from  Brazil,  and  of  the  Carthagena  ipecac,  Cephaelis  acuminata 
(Fam.  Rubiaceoi),  and  it  is  required  to  yield  on  assay  not  less 
than  2  per  cent,  of  alkaloid.  It  contains  3  alkaloids — emetine, 
the  important  one,  and  cephaeline  and  psychotrine. 

Preparations  and  Doses. — The  expectorant  dose  is: 
Ipecac,  i  grain  (0.06  gm.). 
Fluidextract,  i  minim  (0.06  c.c.). 
Syrup,  7  per  cent,  of  fluidextract  (acid  with  acetic  acid),  15 

minims  (i  c.c.). 

Powder  of  ipecac  and  opium  (Dover's  powder),  10  per  cent, 
each  of  ipecac  and  opium,  10  grains  (0.6  gm.). 

The  emetic  dose  is  15  grains  (i  gm.).  The  dose  in  amebic 
colitis  is  30  grains  (2  gm.),  decreased  about  3  grains  (0.2  gm.) 
daily,  and  given  at  bedtime  and  in  enteric  pills  to  prevent 
vomiting;  Morgan  recommends  that  a  liquid  ipecac  preparation 
be  given  through  a  duodenal  tube. 

Emetine  hydrochloride,  freely  soluble  in  water  and  alcohol,  is 
used  subcutaneously  in  doses  of  ^  grain  (0.02  gm.)  one  to  three 
times  a  day.  It  should  not  be  continued  beyond  ten  days,  but 
with  intervals  of  a  few  days  may  be  repeated  for  a  second,  third, 
or  fourth  period  of  a  week  or  ten  days. 

Pharmacologic  Action  of  Emetine. — Microorganisms. — Eme- 
tine in  solutions  of  i  :  100,000  is  destructive  to  both  pathogenic 
and  non-pathogenic  ameba?.  In  strong  solutions  up  to  5  per  cent. 
Kolmer  and  Smith  found  its  bactericidal  value  5  times  that  of 
phenol. 

Skin,  Mucous  Membranes,  and  Alimentary  Tract. — The  drug  is 
irritant  locally.  Applied  to  the  skin  it  has  a  pustulant  action, 
and  in  solutions  of  i  :  500  causes  marked  irritation  of  mucous 


IPECACUANHA  565 

membranes.  Chauffard  set  up  a  violent  irritation  of  the  in- 
testines by  an  irrigation  with  i  :  10,000.  Lyons,  1915,  took  ^ 
grain  (0.03  gm.)  by  mouth,  and  quickly  developed  nausea, 
followed  in  one  hour  by  vomiting,  and  an  hour  later  by  loose 
stools  accompanied  by  griping.  In  oral  administration  nausea 
and  vomiting  come  on  almost  at  once,  yet  may  be  prevented  by 
the  previous  administration  of  a  large  dose,  i  dram  (4  gm.),  of 
bismuth  subnitrate  or  cerium  oxalate.  Much  larger  doses  than 
can  be  borne  by  mouth  must  be  given  subcutaneously  or  even 
intravenously  before  the  development  of  nausea,  vomiting,  or 
diarrhea.  These  effects  would,  therefore,  seem  to  be  essentially 
local.  But  Eggleston  and  Hatcher  have  found  that  in  animals 
with  stomachs  removed  emetine  intravenously  caused  symptoms 
of  nausea  and  the  movements  of  vomiting,  therefore  there  must 
be  a  certain  central  action  as  well.  After  subcutaneous  doses 
Foulkrod  found  emetine  in  the  stomach,  but  Lyons  failed  to 
find  it  in  the  intestines. 

Circulation. — There  is  a  weakening  of  the  heart  muscle  with 
slowing  and  dilatation  similar  to  that  from  chloroform  and  not 
influenced  by  atropine  or  cutting  the  vagi.  Death  may  result 
from  auricular  and  ventricular  fibrillation.  In  the  frog  and  turtle 
heart-block  has  been  observed.  From  therapeutic  doses  there  is 
a  very  short  and  slight  rise  in  arterial  pressure  followed  by  a 
sharp  fall  and  a  quick  return  to  its  former  level.  From  toxic 
doses  there  is  a  progressive  slowing  and  weakening  of  the  heart 
and  fall  in  pressure,  with  collapse.  Pellini  and  Wallace  obtained 
no  change  or  a  slight  contraction  of  the  arteries;  but  Evans, 
Middleton,  and  Smith  say  that  there  is  a  transient  vasoconstric- 
tion  followed  by  definite  vasodilation.  Sollmann  observed  a 
vasomotor  paralyzing  action.  Howell  has  noted  a  deficiency 
in  fibrinogen  in  the  bloccl  as  the  result  of  which  clotting  is 
retarded  and  the  clot  is  not  retractile. 

Respiratory. — There  is  some  depression  from  subcutaneous 
doses,  but  from  intravenous  the  respiratory  center  is  stimulated 
and  the  rate  and  depth  of  respiration  increased  (Pellini  and  Wal- 
lace). From  toxic  amounts  there  is  a  decided  tendency  to 
pulmonary  congestion  or  to  hemorrhagic  pneumonic  consolida- 
tion, with  or  without  hemoptysis. 

Kidneys. — There  is  no  effect  except  in  poisoning,  \vhen  there 
may  be  nephritis  with  albuminuria  and  chloride  and  nitrogen 
retention. 

Toxicology. — There  are  many  reports  of  ill  effects  from  the 
human  use  of  the  drug.  From  ^  grain  (0.03  gm.)  daily  by  hypo- 
dermic for  four  days  Levy  and  Rowntree  report  severe  diarrhea, 
abdominal  pain,  tenesmus,  and  toxic  delirium,  with  recovery,  in 


566  PHARMACOLOGY   AND   THERAPEUTICS 

a  woman  of  95  pounds,  and  death  in  a  man  from  29  grains  (2  gm.) 
given  subcutaneously  in  the  course  of  twenty  days.  They 
caused  death  of  a  dog  by  hemorrhagic  gastro-enteritis  from  £ 
grain  (o.oi  gm.)  subcutaneously  daily  for  three  days.  Spehl  and 
Colard  gave  22  grains  (1.44  gm.)  in  eighteen  days,  when  there 
developed  a  flaccid  paralysis,  especially  of  the  neck  muscles,  fol- 
lowed by  difficulty  in  swallowing,  mastication  and  speech, 
with  edema  of  the  face,  kidney  retention,  and  rapid  weak  heart. 
The  symptoms  subsided  after  stoppage  of  the  drug.  Johnson  and 
Murphy,  1917,  had  two  deaths  of  men  after  the  subcutaneous 
use  of  a  total  of  23!  and  25  grains.  These  amounts  tally  with 
Dalimier's  estimation  from  animal  experiments  that  the  toxic 
dose  for  a  i2o-pound  adult  is  about  27  grains  (1.8  gm.)  whether  it 
is  given  in  a  short  period  or  during  two  or  three  weeks.  Harrison 
reports  a  death  from  the  wine  of  ipecac. 

From  many  reported  cases  a  summary  of  the  toxic  effects  from 
subcutaneous  doses  shows  that  besides  the  pronounced  gastro- 
intestinal irritation  there  may  be  acute  renal  insufficiency, 
general  edema,  hemoptysis,  flaccid  paralysis,  peripheral  neuritis, 
delirium,  coma,  and  failure  of  the  heart. 

There  is  a  consensus  of  opinion  that  intravenous  doses  are 
exceedingly  dangerous,  and  that  if  used  intravenously  at  all  the 
drug  should  be  well  diluted  and  very  slowly  administered. 

Therapeutics. — Ipecac  is  employed  (i)  as  an  expectorant  in  dry 
bronchitis,  laryngitis,  and  rhinitis,  (2)  as  a  nauseant  or  emetic  in 
non-diphtheritic  croup,  (3)  as  a  diaphoretic  in  the  form  of  Dover's 
powder  at  the  onset  of  a  cold  (see  Diaphoretics),  and  (4)  in 
amebic  dysentery  to  supplement  the  subcutaneous  injections  of 
emetine. 

Emetine  has  its  greatest  usefulness  in  the  treatment  of  amebic 
dysentery,  in  which  it  apparently  attacks  the  organisms  in  the 
intestinal  wall.  It  does  not  destroy  the  encysted  forms  found  in 
the  ameba-carriers.  It  is  to  be  borne  in  mind  that  by  prolonged 
use  emetine  itself  may  result  in  diarrhea  or  dysentery.  In 
pyorrhea  alveolaris  it  may  produce  improvement  by  destruction  of 
the  Entameba  buccalis,  but  it  fails  to  cure  because  the  ameba  is 
not  the  cause  of  the  pyorrhea  (U.  S.  Public  Health  Reports,  1916). 
It  has  been  recommended  in  chronic  non-amebic  follicular  enter- 
itis, sprue,  and  some  other  diseases.  Chauffard  employed  it  in 
tuberculous  hemoptysis,  but  neither  clinical  results  nor  its 
pharmacologic  action  justify  its  use  for  any  internal  hemorrhage, 
and  because  of  its  causing  pulmonary  congestion  Zepf  and  others 
believe  it  contraindicated  in  hemoptysis. 


ERGOT  567 

EMMENAGOGUES 

These  are  remedies  which  tend  to  bring  on  the  menstrual 
flow.  They  are: 

1 .  Local  measures,  as  hot  or  mustard  foot-  or  sitz-baths,  hot- 
water  bottle  or  counterirritant  drugs  (turpentine,  mustard)  to 
lower  abdomen,  hot  vaginal  douches. 

2.  Strong  purgatives,  as  aloes,  jalap,  castor  oil. 

3.  Genito-urinary  irritants,  as  cantharis. 

4.  Drugs  which  stimulate  the  uterine  muscle,  as  ergot,  hydrastis, 
quinine,  and  caulophyllum  (blue  cohosh).     Pilcher  found  prompt 
contraction  of  uterine  strips  from  caulophyllum. 

5.  Measures  to  improve  the  general  health,  as  iron,  cod-liver 
oil,  strychnine;  in  heart  disease,  digitalis;  in  tuberculosis,  dry 
cool  air. 

In  early  pregnancy  any  of  these  measures  except  those  of  the 
first  and  last  groups  may  result  in  abortion,  so  an  emmenagogue 
is  also  an  abortifacient.  Such  substances  as  corn-smut,  cotton- 
root  bark,  viburnum,  valerian,  and  the  strong  volatile  oils  (rue, 
tansy,  pennyroyal,  etc.)  have  been  shown  to  be  without  stimulat- 
ing action.  Lieb  states  that  "the  uterine  colic  which  results 
from  irritant  cathartics  or  (so-called)  emmenagogue  oils  is  not 
due  to  direct  stimulation  of  the  uterus,  but  is  purely  reflex." 
Many  volatile  oils  tend  rather  to  overcome  uterine  colic. 

ERGOT 

Ergot  (ergota)  is  a  fungus  which  replaces  the  grain  of  rye. 
It  rapidly  deteriorates  and  should  not  be  more  than  one  year 
old.  Our  supply  comes  from  Europe. 

Constituents. — Though  a  vast  amount  of  study  was  given 
to  ergot  for  many  years,  its  chemistry  remained  in  a  state  of 
great  confusion  until  Dale  and  his  associates  published  their 
admirable  studies  in  1909  and  1910.  We  now  recognize  three 
very  active  alkaloids,  ergotoxine,  beta-iminazolylethylamine,  and 
para-hydroxy-phenylethylamine,  and  two  others,  ergotine  and 
isoamylamine.  In  addition  there  may  be  choline,  and  there  are 
ergotinic  acid,  various  saponins,  and  20  to  35  per  cent,  of  fat. 
A  rare  constituent,  but  one  with  a  powerful  depressant  action 
on  the  circulation,  is  acetylcholine. 

Ergotoxine  is  a  hydrated  ergotine.  It  is  almost  insoluble  in 
water,  but  is  soluble  in  alcohol.  Its  phosphate,  which  is  soluble 
in  water,  is  employed. 

Para-hydroxy-phenylethylamine  (tyramine),  readily  soluble  in 
water,  is  closely  related  to  certain  amines  found  in  unpurified 
cod-liver  oil  as  the  result  of  the  putrefaction  of  the  cod-livers. 


568  PHARMACOLOGY  AND  THERAPEUTICS 

It  also  bears  a  somewhat  close  chemical  relation  to  epinephrine. 
It  may  be  formed  by  the  prolonged  trypsin  digestion  of  egg- 
albumin  (Langestein,  1902),  and  was  obtained  by  the  action  of  a 
culture  of  human  feces  on  broth  to  which  tyrosin  was  added 
(Barger  and  Walpole,  1909);  hence  it  is  probably  a  product  of 
intestinal  putrefaction  in  some  human  cases.  It  has  also  been 
prepared  synthetically. 

Preparations  and  Doses.— 
Ergot,  30  grains  (2  gin.). 
Fluidextract  (acetic),  30  minims  (2  c.c.). 
Extract,  4  grains  (0.25  gm.) 

The  alkaloids  also  may  be  employed — ergotoxine  phosphate 
in  dose  of  -£-$  grain  (0.0012  gm.),  and  tyramine  in  dose  of  \  grain 
(0.03  gm.)  hypodermatically.  They  are  not  irritant.  A  very 
efficient  artificial  mixture  containing  the  three  important  al- 
kaloids in  proper  proportions  to  give  a  pronounced  ergot  action 
is  to  be  had. 

Standardization. — Up  to  the  present  no  chemic  assay  has 
proved  satisfactory.  For  the  biologic  assay  three  chief  meth- 
ods have  been  employed,  viz.,  the  blood-pressure  method, 
which  estimates  the  para-hydroxy-phenylethylamine,  the  uterine 
method  which  estimates  the  beta-iminazolylethylamine,  and  the 
cockscomb  method,  which  estimates  the  ergotine.  The  first  is 
not  good,  the  pressor  effect  giving  no  indication  of  the  con- 
tractile power  of  the  drug  upon  the  uterus.  The  uterine  method 
is  satisfactory,  but  is  expensive  and  tedious.  Edmunds  and  Hale 
and  a  number  of  others  recommend  the  cockscomb  method, 
finding  it  in  very  close  agreement  with  the  uterine  method  and 
much  simpler.  It  is  based  on  the  development  of  a  purple 
hue  in  the  comb  of  a  rooster  from  an  injection  of  ergot.  The 
standard  is  considered  to  be  0.75  c.c.  of  fluidextract  per  kilo, 
equivalent  to  1.87  mg.  of  ergotoxine  phosphate. 

Deterioration. — Ergot  rapidly  deteriorates  unless  kept  from 
the  air,  and  a  number  of  investigators  report  that  ergot  and  ergot 
preparations  are  useless  if  more  than  a  year  old.  Yet  this  is 
not  found  to  be  the  case  in  clinical  experience,  which  corresponds 
more  nearly  with  the  experimental  work  of  Haskell  and  Eckler 
(1912).  They  tested  separately,  and  then  mixed  together,  a 
large  number  of  fluidextracts  made  in  the  different  years.  Those 
one  and  two  years  old  gave  a  reaction  in  the  standard  amount, 
i.  e.j  0.75  c.c.  per  kilo.  Those  three  years  old  required  i  c.c. 
for  the  reaction,  and  those  four  years  old  1.5  c.c.,  and  those  five 
years  old  1.75  c.c. 

Pharmacologic  Action. — The  active  principles  of  ergot  stimu- 
late the  ends  of  certain  sympathetic  nerves  or  their  myoneural 


ERGOT 


569 


junctions.  In  large  amounts  ergotoxine  paralyzes  the  same 
endings. 

Local. — Ergot  is  irritant  to  mucous  membranes  and  raw 
tissues.  It  has  practically  no  constricting  action  on  mucous 
membranes,  but  when  injected  hypo- 
dermatically  produces  a  moderate  con- 
striction of  the  arteries  at  the  point  of 
injection.  In  some  cases  it  has  caused 
local  gangrene. 

Alimentary  Tract. — Preparations  of 
ergot  are  irritant  locally  and  may  cause 
nausea,  or,  in  poisoning,  a  violent  gastro- 
enteritis. The  alkaloids  are  not  irritant. 
The  therapeutic  doses  of  ergot  stimulate 
the  ends  of  the  splanchnic  (inhibitory) 
nerves,  and  cause  decreased  intestinal 
peristalsis.  Very  large  doses  cause  par- 
alysis of  the  same  sympathetic  nerve- 
endings,  and  result  in  increased  peristalsis 
and  activity  of  the  bowels.  This  effect  is 
not  obtainable  in  therapeutics.  In  test- 
ing roosters  it  is  usual  for  their  bowels 
to  move. 

Circulation.  —  (a)  Ergotoxine.  —  In- 
jected intravenously  in  a  dog  in  dose  of 
•^5  grain  (i  mg.)  per  kilo  there  is  a  prompt 
rise  in  arterial  pressure  with  considerable 
slowing  and  weakening  of  the  heart.  A 
second  injection  makes  a  smaller  rise  in 
pressure  or  no  change.  An  injection  of 
epinephrine  at  this  time  causes  dilatation 
of  the  arteries,  the  so-called  "vasomotor 
reversal"  of  Dale.  The  ergotoxine  at 
first  stimulates  and  then  paralyzes  the 
myoneural  junctions  of  the  vasoconstrictor 
nerves,  but  leaves  the  vasodilator  nerves 
untouched. 

(b)  Para-hydroxyphenylethylamine  (ty-     -p\g. 
ramine)  intravenously  results  in  a  prompt 
and  marked  rise  in  arterial  pressure.    This 

effect  differs  from  that  of  epinephrine  in  its  slower  development, 
its  four  or  five  times  as  great  duration,  and  its  production  (at 
least  this  is  a  claim  put  forward)  by  mouth  and  subcutaneous 
doses.  The  constriction  of  the  arteries  at  the  site  of  a  hypoder- 
matic injection  is  less  than  that  from  epinephrine,  but  it  lasts 


67. — Ergotized  rye 
(Maisch). 


570  PHARMACOLOGY  AND   THERAPEUTICS 

longer  and  may  result  in  local  gangrene.  Tests  on  human  arterial 
pressure  have  been  made  by  several  observers.  In  a  patient  of 
Hoyt's  with  myocarditis,  40  mg.  subcutaneously  produced  a  rise 
of  pressure  from  85  to  130  mm.  in  five  minutes,  and  the  pressure 
had  returned  to  its  former  level  in  nineteen  minutes.  By  mouth 
Hoyt  found  that  doses  of  5  and  10  mg.  three  times  a  day,  and 
Clark  that  a  dose  of  100  mg.  repeated  in  forty  minutes,  had  no 
effect. 

(c)  Beta-iminazolylethylamine  intravenously  in  dose  of  ^-$ 
grain  (o.i  mg.)  per  kilo  produces  an  immediate  and  prolonged 
fall  in  blood-pressure  due  to  an  as  yet  unexplained  peripheral 
action.     It  occurs  after  destruction  of  the  central  nervous  sys- 
tem, but  perfusion  of  isolated   arteries  results  in  contraction. 
The  heart  is  slowed,  but  its  output  per  minute  is  increased. 

(d)  The  Whole  Drug. — Though  the  action  of  the  active  prin- 
ciples is,  therefore,  well  known,  the  effect  of  preparations  of  ergot 
itself  upon  the  circulation  is  problematic.     For,  given  intrave- 
nously, ergot  may  induce  a  fall  in  pressure,  as  Sollmann  and 
Brown  (1905)  found  in  350  experiments  on  38  animals;   or  it 
may  cause  a  striking  rise  in  pressure.    The  fall  in  pressure  may 
be  due  to  beta-iminazolylethylamine,  to  acetylcholine,  or  to  the 
saponin  bodies.     In  therapeutics,  it  is  hardly  possible  to  give 
enough  ergot  to  obtain  a  rise  in  pressure,  but  a  hypodermatic  or 
intravenous  of ^tyramine  is  a  practical  method  of  raising  the  arte- 
rial tension  in  emergency. 

Respiration. — After  the  intravenous  injection  of  o.ooi  gm. 
per  kilo  of  ergotoxine,  the  respiratory  center  is  depressed,  as 
shown  by  slow  and  shallow  breathing  or  Cheyne-Stokes  respira- 
tion (Wiggers).  From  broncho-constriction  owing  to  direct 
stimulation  of  bronchial  muscle  (Jackson),  an  intravenous  of 
beta-iminazoylethylamine  in  an  unanesthetized  animal  may 
cause  asthma. 

Uterus. — Though  the  other  principles  stimulate  the  uterus, 
the  very  pronounced  action  of  ergot  is  due  in  large  measure  to 
beta-iminazolylethylamine.  With  a  solution  of  i  :  600,000 
Lieb  obtained  powerful  contraction  with  temporary  tetany. 
The  uterine  constriction  is  promoted  to  a  slight  degree  through  a 
central  action,  but  essentially  through  stimulation  of  the  uterine 
muscle.  In  the  early  stages  of  pregnancy  the  increase  may  be 
seen  in  the  strengthening  of  the  normal  intermittent  contrac- 
tions which  take  place  at  this  time;  and  there  is  a  prevalent 
belief  both  in  the  profession  and  among  the  laity  that  in  the  early 
months  of  pregnancy  ergot  is  abortifacient.  But  experiments 
with  pregnant  animals  have  not  shown  it  to  possess  this  power 
to  any  great  degree;  and  in  pregnant  women,  it  has  very  fre- 


ERGOT  571 

quently  failed  to  have  the  slightest  effect.  It  is  of  considerable 
interest  that  in  some  cases  of  ergotism  pregnancy  has  gone  on  to 
term  without  interruption. 

In  labor,  moderate  doses  tend  to  increase  the  strength  of  the 
normal  intermittent  contractions,  while  large  doses  (i  dram— 
4  gm.)  produce  a  continuous  or  tetanic  contraction  of  the  uterus. 
This  makes  ergot  of  value  after  labor  to  promote  the  normal 
postpartum  uterine  contraction;  but  it  should  not  be  adminis- 
tered until  the  uterus  is  empty,  lest  the  organ  go  into  tetanic 
contraction  and  compress  the  contents  without  expelling  them. 
The  drug  usually  takes  thirty  to  sixty  minutes  to  act  when  given 
by  mouth. 

The  stoppage  of  uterine  hemornhage  is  essentially  due  to 
the  uterine  contraction,  and  is  not  to  any  great  degree,  if  at  all, 
attributable  to  contraction  of  the  uterine  arteries. 

Toxicology. — Acute  poisoning  is  usually  the  result  of  large 
doses  taken  to  produce  abortion.  The  symptoms  are — (i) 
those  of  gastro-enteritis,  with  nausea,  vomiting,  diarrhea,  and 
abdominal  pain,  and  (2)  various  nervous  manifestations,  such 
as  itching,  tingling,  hyperesthesia,  and  anesthesia  of  the  skin, 
mental  depression,  convulsions,  coma,  and  collapse.  The  treat- 
ment is  symptomatic  for  gastro-enteritis  and  collapse.  In  a 
fatal  case  Rosenbloom  and  Schildecker  found  ergotinine  in 
stomach,  intestines,  liver,  and  kidneys. 

Chronic  Poisoning  or  Ergotism. — This  is  not  seen  in  this 
country,  though  it  has  been  in  the  past  common  enough  in  Europe 
from  the  consumption  of  bread  made  from  ergot-infected  rye. 
The  ergotism  manifests  itself  either  by  gangrene  or  by  certain 
pronounced  nervous  symptoms.  The  gangrene  is  caused  by 
persistent  contraction  of  the  arteries  in  some  particular  part  of 
the  body,  chiefly  the  fingers,  toes,  ears,  and  tip  of  the  nose.  But 
there  may  be  sloughing  in  any  part  of  the  body  surface,  or  ulcer 
of  the  stomach,  or  even  gangrene  of  the  lung  or  of  the  uterus. 
The  small  arteries  of  the  part  are  found  to  contain  hyaline  plugs, 
as  in  any  case  of  dry  gangrene.  The  nervous  type  shows  in  gastro- 
intestinal disturbances,  itching  of  the  skin,  headache,  dizziness, 
disordered  vision,  temporary  or  permanent  blindness,  drowsiness, 
mental  depression,  and  clonic  or  epileptiform  convulsions  which 
may  leave  permanent  contractures  in  hands,  feet,  arms,  legs,  or 
trunk.  These  manifestations  are  thought  to  be  due  to  spasm 
in  the  arteries  of  the  central  nervous  system;  the  permanent 
effects  are  due  to  softening  from  the  shutting  off  of  the  arteries. 
Fuchs  has  pointed  out  that  ergot  is  a  cause  of  endemic  tetany. 

Therapeutics. — The  main  employment  of  ergot  is — (i)  To 
prevent  postpartum  hemorrhage,  which  it  does  by  inducing  uterine 


572  PHARMACOLOGY   AND   THERAPEUTICS 

contraction  rather  than  by  narrowing  the  vessels;  (2)  to  check 
menorrhagia,  and  (3)  to  overcome  subinwlulion  of  the  uterus. 
Though  it  has  been  used  for  hemorrhage  from  stomach,  lungs, 
kidneys,  etc.,  there  is  no  indication  that  a  therapeutic  dose  pro- 
duces constriction  of  the  arteries  in  these  regions.  In  any  dose 
whatever  it  does  not  constrict  the  pulmonary  arteries. 

It  has  been  employed  to  raise  blood-pressure,  but  for  this 
purpose,  as  we  have  seen,  the  active  principles  are  to  be  used, 
and  not  ergot  itself.  Thus  tyramine  might  be  employed  in  shock 
or  collapse.  To  obtain  arterial  constriction,  Wiggers  used  -^ 
grain  (o.ooi  gm.)  of  ergotoxine  phosphate  per  kilo  in  dogs.  He 
advised  that  the  dose  should  not  be  repeated,  as  the  paralysis 
of  the  nerve-endings  might  come  on. 

On  empiric  grounds  ergot  has  been  proposed  for  a  great 
many  different  conditions;  for  example,  it  is  spoken  highly  of  in 
diabetes  insipidus,  enuresis  nocturna,  and  delirium  tremens. 
The  author  found  it  useless  in  diabetes  mellitus  and  the  night- 
sweats  of  tuberculosis.  Ransom  speaks  highly  of  it  in  delirium 
tremens.  (See  Alcohol.) 

Ergotoxine  is  employed  in  physiologic  experimentation  to 
paralyze  sympathetic  nerve-endings,  especially  the  vasocon- 
strictors. 

HYDRASTIS 

Hydrastis,  or  goldenseal,  is  the  dried  rhizome  and  roots 
of  Hydrastis  canadensis  (Fam.  RanunculacecE) ,  yielding,  when 
assayed,  not  less  than  2.5  per  cent,  of  hydrastine.  It  is  a  small 
herb  of  the  eastern  United  States. 

Constituents. — Three  alkaloids:  hydrastine,  2.5  per  cent.; 
berberine,  3  to  4  per  cent.,  and  a  little  canadine;  in  addition, 
some  resinous  material. 

Preparations. —  Hydrastis,  30  grains  (2  gm.).  Fluidextract  (2 
per  cent,  hydrastine),  30  minims  (2  c.c.).  Glycerite  (1.2  per 
cent,  hydrastine),  30  minims  (2  c.c.).  Tincture  (0.4  per  cent, 
hydrastine),  i  dram  (4  c.c.).  Hydrastine  and  hydrastine  hydro- 
chloride,  ^  grain  (o.oi  gm.).  The  hydrochloride  is  freely  soluble 
in  water  and  alcohol. 

Pharmacologic  Action. — Local. — It  has  a  slightly  astringent 
action,  and  in  some  sections  is  employed  as  a  stimulant  of  mucous 
membranes  in  chronic  catarrhal  conditions,  as  of  nose,  throat, 
urethra,  and  vagina. 

Alimentary  Tract. — It  has  a  bitter  effect  upon  appetite. 
Through  a  central  action  it  increases  the  motor  and  secretory 
activity  of  the  stomach  and  promotes  intestinal  peristalsis.  Large 
doses  cause  vomiting  and  diarrhea. 


HYDRASTININE    HYDROCHLORIDE  573 

Nervous  System. — On  the  medulla  and  cord,  hydrastine  acts 
mildly  like  strychnine,  stimulating  slightly  the  respiratory,  vagus, 
and  vasoconstrictor  centers  and  increasing  reflex  irritability. 
Very  large  doses  cause  tonic  and  clonic  convulsions,  incoordina- 
tion,  and  depression  of  the  medullary  centers. 

Eye. — Locally  applied,  it  first  contracts  then  dilates  the  pupil. 

Circulation. — Lieb  says  that  after  a  momentary  and  negligible 
rise  small  doses  produce  a  slight  but  persistent  fall  in  arterial 
pressure.  The  heart  rate  is  practically  unchanged. 

In  poisoning,  the  centers  are  depressed,  and  the  heart  becomes 
slow  and  feeble  from  direct  action  on  the  cardiac  muscle.  At  the 
same  time  the  muscles  in  the  arterioles  become  depressed  and  the 
vessels  dilate;  hence  blood-pressure  is  very  low.  It  differs 
materially  from  strychnine,  as  this  tendency  to  depress  the  heart 
is  manifested  before  convulsions  come  on. 

Respiratory. — Ordinarily,  the  respiratory  center  is  stimulated ; 
but  in  poisoning  it  is  depressed,  and  death  takes  place  from  as- 
phyxia brought  on  by  paralysis  of  the  respiratory  center  or  by 
the  convulsions. 

Muscle. — Muscular  tissue  of  all  kinds  (except  perhaps  the 
uterus)  is  primarily  stimulated,  then  depressed. 

Uterus. — Hydrastis  resembles  ergot  in  its  tendency  to  in- 
crease the  normal  contraction  of  the  uterus,  but  it  is  much  less 
powerful  in  bringing  about  contraction  of  the  postpartum  uterus. 
In  menorrhagia  or  metrorrhagia  from  fibroids,  subinvolution,  or 
relaxed  uterus,  it  may  arrest  hemorrhage.  The  uterine  effect  is 
due  to  both  the  hydrastine  and  the  berberine. 

Elimination. — Hydrastine  is  excreted  in  the  urine  as  such, 
no  hydrastinine  being  formed  in  the  body.  Slight  amounts  also 
appear  in  the  saliva  and  feces. 

Therapeutics. — Hydrastis  has  been  much  employed  locally 
in  chronic  catarrh  of  nose,  throat,  urethra,  and  vagina.  Owing 
to  the  large  amounts  of  bitter  alkaloids,  it  is  a  powerful  bitter. 
It  is  also  employed  in  postpartum  hemorrhage,  subinvolution, 
menorrhagia,  and  metrorrhagia,  whether  caused  by  fibroids  or 
not. 

HYDRASTININE   HYDROCHLORIDE 

This  salt  (hydrastinine  hydrochloridum) ,  CnHnNOz-HCl,  is 

the  hydrochloride  of  an  artificial  alkaloid  formed  by  the  oxidation 
of  hydrastine.  Dose,  \  grain  (0.03  gm.).  It  is  freely  soluble  in 
water  and  alcohol.  Hydrastinine  has  a  local  constricting  effect 
on  arteries,  and  has  the  same  action  on  centers  as  hydrastine; 
but  it  has  little  if  any  effect  in  depressing  the  heart  and  other 
muscles.  It  induces  a  rise  in  blood-pressure  through  stimulation 


574  PHARMACOLOGY   AND   THERAPEUTICS 

of  the  vasoconstrictor  center.  It  causes  rapid  dilatation  of  the 
pupil,  the  effect  wearing  off  inside  of  twenty-four  hours. 

It  is  for  its  action  on  the  uterus,  however,  that  hydrastinine 
is  employed,  as  it  tends  to  stop  hemorrhage  by  stimulating  the 
uterus  itself.  It  is  not  so  good  as  ergot  in  postpartum  hemorrhage, 
but  is  largely  employed  in  subinvolution,  in  late  hemorrhage  fol- 
lowing parturition,  and  in  profuse  menstruation,  whether  caused 
by  fibroids  or  not.  A  10  per  cent,  solution  has  been  employed 
locally  on  cotton  in  hemorrhage  from  nose,  mouth,  rectum,  and 
uterus. 

Cotarnine  hydrochloride,  stypticin,  is  oxymethyl-hydrastinine ; 
dose,  \  grain  (0.03  gm.).  It  is  prepared  from  narcotine,  and  has 
an  action  practically  like  that  of  hydrastinine,  but  with  a  hydras- 
tine  tendency  to  depress  the  heart  muscles,  and  a  mild  narcotic 
action.  Its  uses  are  those  of  hydrastinine. 

CARBON   MONOXIDE 

This  gas  (CO)  becomes  of  interest  from  the  frequency  of  its 
poisoning.  Most  of  the  cases  result  from  illuminating-gas, 
which  contains  6  to  10  per  cent.,  and  is  frequently  inhaled  with 
suicidal  intent.  But  some  come  from  defective  flues  of  furnaces, 
coal  stoves,  charcoal  fires,  blast  furnaces,  and  the  "after-damp" 
of  mines  and  old  wells. 

The  gas  has  great  affinity  for  hemoglobin,  and  prevents  the 
formation  of  oxyhemoglobin  unless  oxygen  is  present  in  very 
great  excess.  But  the  compound  is  not  a  very  stable  one  and 
usually,  if  respiration  is  good  and  oxygen  plentiful,  splits  up  so 
that  all  the  carbon  monoxide  will  be  exhaled  by  the  lungs  in  from 
one  to  three  hours.  The  monoxide  does  not  oxidize  to  carbon 
dioxide  in  the  body.  Except  for  its  affinity  for  hemoglobin  the 
gas  is  physiologically  harmless. 

The  action  of  the  gas  is  asphyxial,  the  exclusion  of  oxygen 
from  the  tissues,  particularly  the  central  nervous  system,  being 
the  cause  of  the  symptoms.  Haldane  found  that  when  mice 
were  placed  in  oxygen  under  two  atmospheres  pressure,  so  that 
the  plasma  would  carry  enough  oxygen  to  maintain  life,  carbon 
monoxide  had  no  toxic  effect;  but  that  when  the  oxygen  pressure 
was  removed  by  exposing  the  mice  to  the  air,  poisoning  followed. 
The  toxic  symptoms  are,  therefore,  due  to  an  interference  with 
the  oxygen-carrying  power  of  the  blood.  The  blood  of  a  man  at 
rest  may  become  nearly  one-third  saturated  without  his  realizing 
that  anything  is  wrong  (Henderson) ;  and  in  a  few  hours  he  is  as 
lit  for  vigorous  exertion  as  before.  Haldane  observed  that  death 
occurs  when  about  80  per  cent,  of  the  hemoglobin  is  disabled, 
and  that  the  best  remedy  is  the  inhalation  of  pure  oxygen. 


CARBON   MONOXIDE  575 

The  symptoms  are  those  of  stimulation  of  the  cerebrum  and 
medullary  centers,  followed  by  their  depression.  At  first  there 
are  headache,  dizziness,  mental  excitement  or  delirium,  slow 
pulse  from  stimulation  of  the  vagus  center,  raised  arterial  pres- 
sure from  stimulation  of  the  vasoconstrictor  center,  dyspnea  from 
stimulation  of  the  respiratory  center,  and  nausea  and  vomiting 
from  stimulation  of  the  vomiting  center.  These  may  be  fol- 
lowed by  mental  dulness  or  coma,  prostration,  rapid  weak  pulse, 
lowered  blood-pressure,  slow  and  shallow  or  Cheyne-Stokes 
respiration,  fever,  loss  of  control  of  the  sphincters,  and  convul- 
sions, usually  of  cerebral  (epileptiform)  type.  The  heart  con- 
tinues to  beat  after  respiration  has  ceased.  In  the  late  stages 
there  is  sometimes  great  spasticity  or  muscular  rigidity,  so  that 
the  patient  seems  as  "stiff  as  a  board."  Spiller  and  others  find 
this  associated  with  bilateral  softening  of  the  inner  segments  of 
the  lenticular  nuclei,  the  softening  being  due  to  changes  in  the 
minute  supplying  arteries.  Henderson  noted  a  marked  acidosis, 
but  obtained  no  amelioration  of  the  symptoms  after  large  intra- 
venous infusions  of  3  per  cent,  sodium  bicarbonate. 

A  striking  characteristic  of  the  poisoning  is  a  subsidence  of 
the  acute  symptoms,  followed  by  apparent  recovery,  and  then 
some  hours  or  days  later  the  appearance  of  serious  disturbances 
of  the  nervous  system,  showing  in  loss  of  vision,  mental  derange- 
ment, peripheral  neuritis,  paralyses,  epileptiform  convulsions,  or 
collapse  and  death.  There  may  be  permanent  cardiac  weakness. 

Acute  poisoning  is  divided  by  McCombs  (1912),  who  has  seen 
1000  cases,  into  three  stages,  viz.: 

1.  Before  the  patient  loses  consciousness.     It  is  the  stage  of 
stimulation. 

2.  After  the  patient  loses  consciousness,  respiration  still  per- 
sisting.    This  is  the  stage  of  depression.     In  this  stage  or  later, 
cherry-red  spots  over  the  cheek-bones,  neck,  trunk,  and  thighs 
may  make  their  appearance,  and  there  may  be  petechiae. 

3.  Patient    unconscious,    no    spontaneous    respiration.     The 
heart  is  rapid,  weak,  intermittent. 

Chronic  poisoning  occurs  from  the  leakage  of  gas  tubes, 
gas-heated  irons,  or  other  continued  exposure.  It  shows  in 
nausea,  headache,  dizziness,  mental  depression,  lassitude, 
anemia,  loss  of  appetite  and  of  flesh  and  strength,  and  gastric  dis- 
turbances. It  may  give  any  of  the  symptoms  of  the  first  stage 
of  acute  poisoning.  McCombs,  \vho  has  studied  the  men  of  gas 
companies,  reports  polycythemia  as  quite  common,  and  calls 
attention  to  the  fact  that  there  are  many  men  who  have  been 
much  exposed  to  the  gas  for  many  years  without  any  special 
sign  of  ill  health. 


576  PHARMACOLOGY  AND  THERAPEUTICS 

Treatment. — i.  Of  first  importance  in  the  mild  poisoning  is 
fresh  air,  and  in  the  severe  degrees,  oxygen,  under  pressure,  if 
possible. 

2.  Artificial  respiration  when  required,  deep  breathing  being 
essential  to  the  elimination  of  the  gas. 

3.  Maintenance  of  body  warmth. 

4.  For  the  nausea  of  the  mild  type  effervescing  drinks,  and 
for  the  headache  a  carminative,  such  as  aromatic  spirit  of  am- 
monia. 

5.  Transfusion  of  blood   after  a  preliminary  blood-letting, 
with  manipulation  of   the   heart   and  artificial   respiration,  is 
the  method  recommended  by  Crile  and  Lenhart,  who  experi- 
mented on  1 6  dogs,  giving  carbon  monoxide  until  respiration 
ceased. 

Yandell  Henderson  (1916)  says  that  neither  blood-letting 
nor  transfusion  can  be  of  use,  as  the  symptoms  are  not  due  to 
retained  gas.  He  found  that  within  one  or  two  hours  after 
the  patient  had  been  removed  to  fresh  air  the  amount  of  carbon 
monoxide  in  the  blood  was  far  below  the  harmful  percentage. 
The  damage  to  the  nerve-centers  results  from  lack  of  oxygen,  and 
has  already  been  done  when  the  patient  is  rescued. 

BENZINE  AND   GASOLINE 

The  benzine  of  the  Pharmacopoeia  has  a  specific  gravity  of 
0.638-0.660  at  25°  C.  and  is  known  commercially  as  petroleum 
ether.  Commercial  benzine  has  a  specific  gravity  of  about  0.746 
and  commercial  gasoline  of  0.699  to  0.713.  All  are  spoken  of  by 
the  producers  as  "naphtha."  Mixtures  of  commercial  benzine 
and  air,  containing  2.4  to  4.9  per  cent.,  are  explosive.  Benzine 
does  not  dissolve  phenol,  but  benzene  (benzol)  does. 

Benzine  and  gasoline  are  absorbed  fairly  well  through  the 
lungs  and  with  difficulty  from  the  stomach.  They  are  eliminated 
mostly  by  the  lungs  and  slightly  by  the  kidneys.  In  acute 
poisoning  the  most  notable  effect  is  great  congestion  with  exten- 
sive hemorrhages,  or  edema  of  the  lungs  causing  suffocative 
dyspnea  and  frothy  expectoration  of  thin  bloody  liquid.  There 
are  also  congestion  of  brain,  liver,  and  kidneys,  and  a  cherry  red 
color  to  the  blood  resembling  that  in  carbon  monoxide  poisoning. 
The  treatment  is  lung  ventilation,  oxygen,  and  transfusion  of 
blood.  Burgh  reported  the  death  in  four  hours  of  an  eighteen- 
months-old  child  after  swallowing  a  little  more  than  an  ounce  of 
benzine.  Jaffe  reports  the  death  of  a  child  twenty-one  months 
old  from  a  mere  sip,  and  complete  absence  of  symptoms  in 
adults  from  as  much  as  if  ounces  (50  c.c.).  Chronic 


BENZOL  577 

is  believed  to  result  from  inhalation  of  the  gas  by  workers  in  the 
distilleries.  It  leads  to  connective-tissue  changes  in  lungs,  liver 
and  kidneys,  and  perhaps  of  other  organs. 


BENZOL 

Benzol  (benzene,  C6H6)  is  a  colorless,  inflammable  liquid,  in- 
soluble in  water,  soluble  in  4  parts  of  alcohol,  and  freely  miscible 
with  the  oils.  It  is  a  solvent  for  phenol,  a  property  by  which  it 
can  be  differentiated  from  benzine.  Sellings  (1910)  reported 
7  cases  of  purpura  haemorrhagica  in  tin  workers  who  used  a  benzol 
preparation  as  a  substitute  for  solder.  Santesson  (1897)  and 
also  McClure  (1916)  reported  series  of  cases  of  aplastic  anemia 
from  the  use  of  benzol  as  a  solvent  for  rubber.  Following  Sellings 
work  v.  Koranyi  applied  benzol  to  the  treatment  of  leukemia. 

In  experimental  work  on  rabbits  by  Sellings  and  others,  there 
has  been  noted  a  primary  rise  in  the  leukocyte  count  followed  by 
an  irregular  fall,  after  which  there  may  be  a  secondary  rise  and  a 
secondary  fall,  and  finally  a  return  to  normal  when  the  drug  is 
stopped.  The  blood-forming  tissues,  the  bone-marrow,  spleen, 
lymph-nodes,  and  lymph-follicles  are  rendered  aplastic,  and  may 
become  atrophic.  The  result  is  an  aplastic  anemia  with  diminu- 
tion in  the  number  of  blcod-platelets  and  white  cells,  the  poly- 
nuclear  count  being  relatively  more  affected  than  the  mono- 
nuclear.  The  liver  and  kidneys  show  fatty  changes,  and  in  some 
animals  there  are  hemorrhages  into  the  wall  of  the  stomach  and 
intestines  and  into  the  lungs.  After  stopping  the  benzol, 
Sellings  found  complete  regeneration  of  the  aplastic  organs  in 
ten  to  twenty-one  days. 

The  red  blood-cells  may  be  increased  primarily,  but  they  soon 
show  the  effects  of  the  bone-marrow  aplasia  in  a  progressive 
anemia,  with  hemoglobin  index  about  i  and  pratical  absence  of 
nucleated  red  cells.  Musser  and  Krumbhaar  in  6  rabbits  could 
not  produce  purpura,  though  they  obtained  the  characteristic 
anemia  and  leukopenia.  With  the  use  of  benzol  there  is  an 
increase  in  the  phenols  of  the  urine. 

Benzol  is  not  a  cure  for  leukemia,  but  may  be  looked  upon  as  a 
symptomatic  remedy.  There  are  wide  differences  in  individual 
tolerance  to  the  drug,  so  that  the  dose  is  uncertain.  The  begin- 
ning dose,  however,  may  be  put  at  8  minims  (0.5  c.c.)  three 
times  a  day,  and  this  amount  is  rapidly  increased  to  double. 
It  may  be  given  after  meals  in  milk,  or  in  capsules  with  equal 
parts  of  olive  oil.  Mixed  with  olive  oil  it  has  also  been  used 
subcutaneously  and  by  rectum,  but  it  is  irritant.  Winslow  and 
Edwards  (1917)  gave  it  intravenously  to  dogs  and  rabbits,  with 

37 


578  PHARMACOLOGY   AND   THERAPEUTICS 

immediate  agitation,  convulsions,  and  if  the  dose  were  large 
enough,  death.  The  lethal  dose  for  2  dogs  weighing  25  and  29 
pounds  was  45  minims  (3  c.c.).  In  man  it  must  not  be  employed 
intravenously.  If  the  leukocytes  show  a  rapid  fall  in  number, 
the  benzol  should  be  stopped  no  matter  how  high  the  count,  for 
this  is  an  indication  of  severe  aplasia.  The  author  had  one  case 
(demonstrated  by  Dr.  J.  H.  Larkin  at  the  New  York  Pathological 
Society)  with  over  1,000,000  white  cells  per  cubic  millimeter. 
The  benzol,  45  minims  (3  c.c.)  daily,  was  stopped  when  the  leuko- 
cytes fell  rapidly  to  about  200,000,  but  rapid  progress  downward 
continued,  and  when  the  count  reached  10,000  the  patient  died. 
The  bone-marrow  was  very  red,  and  showed  crowded  myelocytes 
with  much  new  connective  tissue,  new  vessels,  and  hemorrhages. 
Billings  and  others  have  noted  basophilic  granular  degeneration 
of  the  lymphocytes.  In  the  two  fatal  poisoning  cases  of  Sellings 
series  the  leukocytes  fell  to  480  and  140  per  cubic  millimeter. 
From  the  use  of  the  drug  in  leukemia  Neumann  reports  a  drop  of 
white  cells  to  200.  Other  untoward  effects  from  its  medicinal 
use  are  heart-burn,  flatulence,  nausea,  vomiting,  diarrhea, 
bronchial  irritation,  minute  hemorrhages  of  skin  and  mucous 
membranes  (purpura  haemorrhagica) ,  albuminuria,  ringing  in  the 
ears,  and  dizziness. 

In  addition  to  lymphoid  and  myeloid  leukemia,  benzol  has 
been  recommended  in  pseudoleukemia  and  polycythemia.  Ki- 
ralyfi  reports  no  effect  in  Banti's  disease,  and  the  most  marked 
effect  in  lymphoid  leukemia.  Others  have  noted  the  best 
effects  in  myeloid  leukemia,  and  Sellings  found  experimentally 
that  the  myeloid  tissues  were  most  affected.  In  the  severe 
aplastic  anemia  of  benzol  poisoning  McClure  obtained  recovery  in 
one  case  by  repeated  transfusions  of  blood  to  the  number  of  five. 

OXYGEN 

Oxygen  gas  (oxygenium)  is  marketed  under  compression  in 
steel  containers.  It  is  regularly  used  by  inhalation,  but  has 
also  been  employed  subcutaneously,  intravenously,  and  intra- 
abdominally.  For  inhalation  it  is  passed  through  water  or 
alcohol  in  a  bottle,  and  conveyed  to  the  patient  by  tubing 
terminating  either  in  a  nose-piece  to  be  inserted  into  the  nostril, 
or  in  a  funnel  to  be  held  before  the  face.  It  tends  to  dry  the 
membranes,  so  if  continued  for  any  length  of  time  should  be 
accompanied  by  the  steam  from  a  croup  kettle. 

Action. — The  inhalation  of  oxygen  in  health  has  no  effect 
on  metabolism,  or  on  the  character,  frequency,  or  depth  of  res- 
piration, but  it  regularly  reduces  the  rate  of  the  heart  and  tends 
to  raise  arterial  pressure. 


!$£,      ••"**'    A     '^'*:.<    \.?|.'.V* 

;.•    .  %»  •  •  •  .'-Lv-V-^^ 


Fig.  68. — Bone-marrow  of  rabbit  after  long  treatment  with  benzol.    Practically 
all  the  blood-forming  elements  are  destroyed  (MacCallum). 


OXYGEN  579 

Kraus  reports  that  in  cardiac  failure  the  amount  of  oxygen 
taken  up  by  the  blood  and  of  CO2  given  off  is  practically  un- 
changed. Leonard  Hill  says  that  breathing  pure  oxygen  has  little 
effect  on  the  capillary  oxygen  tension,  and  Zuntz  and  Schumberg 
produced  experimental  polypnea  and  found  that  the  greatly  in- 
creased amount  of  oyxgen  taken  into  the  lungs  caused  no  altera- 
tion in  the  quantity  of  oxygen  taken  into  the  blood.  Yet  Starling 
says  that  the  normal  oxygen  in  the  blood  and  plasma  is  about  15.6 
per  cent.,  and  that  on  breathing  pure  oxygen  for  a  short  time 
the  percentage  rises  to  19.9  per  cent.  In  cases  of  cyanosis, 
however,  where  the  oxygen  tension  of  the  alveolar  air  is  low  and 
the  CO2  tension  in  the  blood  is  high,  the  ability  of  the  blood  to 
take  up  oxygen  is  diminished;  yet  administered  oxygen  tends  to 
drive  out  the  carbon  dioxide.  Peabody  observed  that  in  pneu- 
monia the  oxygen-carrying  power  of  the  blood  falls  as  the  disease 
progresses. 

Bence  found  that  in  cases  of  cyanosis,  oxygen  reduced  the 
viscosity  of  the  blood  and  so  favored  the  circulation;  and  Stewart 
noted  that,  in  a  case  of  emphysema,  chronic  bronchitis,  and  recur- 
ring cyanosis,  it  increased  the  blood-flow  in  the  hands  from  30  to 
70  per  cent.,  though  it  brought  about  no  especial  changes  in  the 
respiratory  movements.  Hill  and  Flack  have  noted  that  after 
hard  boxing-bouts  of  men  not  in  good  training,  the  inhalation  of 
oxygen  reduced  the  pulse-rate  almost  to  normal,  abolished  the 
shallow,  hurried  breathing,  and  prevented  the  stiffness  of  the 
muscles  which  otherwise  would  have  followed  on  the  next  day. 
It  has  been  used  in  other  athletic  exercises  with  similar  results, 
and  in  mountain-climbing  the  inhalation  of  oxygen  has  proved 
preventive  of  "mountain-sickness,"  which  overcomes  those  not 
inured  to  hard  work  at  high  altitudes. 

Karstner  (1916)  determined  that  atmospheres  containing 
80  to  90  per  cent,  of  oxygen  produce  in  rabbits  in  twenty- four 
to  forty-eight  hours  congestion,  edema,  epithelial  degeneration 
and  desquamation,  fibrin  formation,  and  finally  a  fibrinous 
bronchopneumonia  probably  of  irritative  origin.  There  were  no 
undesirable  effects  except  the  local  ones  in  the  lungs.  It  is 
possible  that  the  local  irritation  is  due  in  part  to  the  low  humidity 
of  the  artificial  atmosphere.  Karstner  and  Ash  (1917)  found 
that  atmospheres  with  up  to  60  per  cent,  of  oxygen  produced  no 
pathologic  changes. 

Therapeutics. — The  net  results  of  the  researches  give  us  the 
impression  that  while  oxygen  inhalation  has  little  measurable 
effect  in  normal  persons,  it  may  have  a  distinct  value  in  cases  of 
oxygen  want,  i.  e.,  those  cases  in  which  the  oxygen  tension  of  the 
alveolar  air  is  low,  or  there  is  hindered  passage  of  oxygen  through 


580  PHARMACOLOGY  AND  THERAPEUTICS 

the  alveolar  walls,  so  that  the  oxygen  tension  in  the  blood  is 
below  normal.  Add  to  this  also  the  effect  of  increased  oxidation 
in  lessening  acidosis,  and  the  revival  value  of  fresh  oxygen  to  the 
diseased  alveolar  and  capillary  tissues,  and  it  would  seem  that 
oxygen  is  a  good  therapeutic  agent  in  gas-poisoning,  pneumonia, 
edema  of  the  lungs,  severe  bronchial  asthma,  heart  failure,  collapse 
in  general  anesthesia,  and  possibly  uremia.  Undoubtedly  its 
best  effect  is  seen  in  conditions  with  cyanosis.  In  the  night  dysp- 
nea of  heart  cases  most  striking  effects  are  reported  by  Macken- 
zie, who  uses  a  hat  box  over  the  head  with  a  hole  for  the  neck, 
and  directs  a  stream  of  oxygen  into  this  for  fifteen  or  thirty 
minutes  at  bedtime.  Haldane  says  that  in  carbon  monoxide 
poisoning  pure  oxygen  rapidly  drives  out  the  poisonous  gas. 
Pure  oxygen  should  not  be  used  continuously  for  more  than 
half  an  hour,  but  it  may  be  employed  continuously  to  enrich 
the  air  which  the  patient  breathes. 


PART  III 
PRESCRIPTION  WRITING 

FOR  three  obvious  reasons  the  writing  of  prescriptions  is  the 
dread  of  the  young  medical  practitioner.  The  reasons  are:  (i) 
His  fear  that  he  may  not  express  his  desires  correctly;  (2)  his 
distrust  in  his  ability  to  make  satisfactory  combinations  or 
palatable  mixtures;  and  (3)  his  anxiety  lest  a  faulty  construction 
should  make  him  the  subject  of  the  pharmacist's  criticisms. 

A  prescription  (pr<z,  scriptum,  written  for)  is  a  physician's 
order  to  the  pharmacist  directing  him  to  furnish  for  a  patient 
one  or  more  remedies  dispensed  in  some  special  form.  The 
first  essential,  therefore,  in  prescription  writing  is  clearness  of 
meaning,  so  that  the  pharmacist  will,  without  any  doubt,  under- 
stand correctly  the  physician's  desires.  Important  on  the  part 
of  the  physician  is  familiarity  with  weights  and  measures,  the 
symbols  employed  in  prescription-writing,  and,  to  some  extent, 
Latin  construction  and  case-endings.  A  table  of  weights  and 
measures  is  to  be  found  in  Part  I.  The  symbols  employed  and 
the  methods  of  expressing  amounts  are  as  follows : 

In  metric  prescriptions  the  amounts  are  expressed  by  simple 
abbreviations  and  Arabic  numerals,  with  fractions  expressed  as 
decimals,  e.  g.,  gm.  6.5,  c.c.  0.6.  In  the  United  States  it  is  under- 
stood that  solids  are  weighed  and  liquids  measured,  so  that  the 
terms  gm.  and  c.c.  may  be  omitted.  An  excellent  way  of  avoid- 
ing the  writing  of  periods,  which  occasionally,  in  hurried  writing, 
may  resemble  the  figure  i ,  is  to  draw  a  vertical  line  and  place  to 
the  left  of  it  all  whole  numbers  referring  to  grams  or  cubic  centi- 
meters, and  to  the  right  of  it  all  fractions.  Thus,  in  the  follow- 
ing formula,  three  ways  of  expressing  the  amounts  are  shown,  viz. : 

1$      Strychninas  sulphatis 0.06  gm.  0.06  o  I  06 

Arseni  trioxidi o.i    gm.  o.i  o  I   i 

Massae  ferri  carbonatis 8.0    gm.  8.0  8  |  o 

Misce  et  fiant  capsula;  No.  xxx. 

In  prescriptions  of  the  apothecaries'  system  the  amounts  are 
expressed  by  certain  special  symbols  and  Roman  numerals. 
The  symbols  commonly  employed  are:  gr.  =  grain  or  grains; 
gtt.  =  drop  or  drops;  n\  =  minim  or  minims;  9  =  scruple  or 
scruples;  3  =  dram  or  drams;  5  =  ounce  or  ounces;  lb- 

581 


582  PHARMACOLOGY   AND   THERAPEUTICS 

=  pound  or  pounds;  0  =  pint  or  pints  (from  octavius.  one- 
eighth  of  a  gallon) ,  and  Cong.  (Congius)  =  gallon  or  gallons.  As 
solids  are  weighed  and  liquids  measured,  it  is  superfluous  to  pre- 
fix /  before  the  dram  and  ounce  signs,  as  f  3 ,  f  5 ,  to  indicate  flui- 
dram,  fluidounce.  The  symbol  for  scruple  9  is  dropping  out  of 
use  because  in  written  prescriptions  it  has  frequently  been  mis- 
taken for  5  (dram). 

In  printing  Roman  numerals  of  prescriptions  small  letters 
are  employed  as:  iv  =  4,  xlviii  =  48.  In  writing,  small  letters 
are  used  for  one  (i  or  j),  five  (v),  and  ten  (x),  and  capitals  for  50 
(L),  100  (C),  and  1000  (M);  and  it  is  customary  to  draw  a  line 
above  all  the  letters  making  up  the  number,  the  dots  of  i  and  j 
being  put  above  this  line;  for  example,  xviij.  In  a  number 
with  terminal  one,  as  one,  two,  three,  seven,  or  eight,  the  last 
letter  is  printed  j,  or  written  as  i  with  a  stroke  projecting  below 
the  line,  e.  g.,  ij,  iij,  vij.  This  is  to  signify  that  it  is  terminal. 
Errors  have  been  made  because  of  a  comma  inadvertently  added, 
and  even  because  of  some  mark,  such  as  a  fly-speck,  upon  the  paper. 
The  dot  over  the  terminal  one  is  an  additional  check;  for  if  all 
the  letters  i  and  j  are  not  dotted,  the  pharmacist  may  be  in  doubt 
as  to  the  number  intended.  As  v,  x,  1  and  c  are  not  dotted  letters, 
it  is  incorrect  to  place  dots  over  them. 

In  expressing  fractions  in  the  apothecaries'  system,  one-half 
is  printed  ss,  and  written  ss  or  fs,  the  manuscript  double  s.  It 
is  an  abbreviation  of  the  Latin  semis.  Other  fractions  are  written 
in  Arabic  numerals  as  vulgar  fractions,  e.  g.,  ^-,  i,  ^.  Fractions 
other  than  one-half  are  not  employed  with  terms  other  than  grain 
or  minim.  Thus,  while  5iss  is  good  usage,  5i  1  is  not,  and  should 
be  expressed  as  5i  gr.  xii,  or  as  gr.  Ixxij. 

A  typical  example  of  an  ordinary  liquid  prescription  is: 

FOR  MRS.  WILSON,  April  20,  1913. 

1^;      Bismuthi  subnitratis 5ij 

Misturae  creta,' q.  s.  ad  oiij 

M.  et  Sig. —  5ij  with  a  little  water  every  three  hours. 

W.  M.  JOHNSON,  M.D. 

Interpreted,  this  would  read:  Take  two  drams  of  the  sub- 
nitrate  of  bismuth  and  a  sufficient  quantity  of  chalk  mixture  to 
make  the  total  measure  three  ounces,  mix  them  together  (accord- 
ing to  the  art  of  pharmacy),  and  on  the  label  write,  "Two  tea- 
spoonfuls  with  a  little  water  every  three  hours." 

According  to  custom,  a  prescription  is  written  in  six  sections, 
viz.: 

i.  The  name  of  the  patient  and  the  date.  (The  name  is 
omitted  from  a  prescription  for  venereal  disease,  or  where  it  is 


LIQUID    PRESCRIPTIONS  583 

best  for  esthetic  reasons,  as  in  prescribing  a  vaginal  douche.) 
The  pharmacist  is  expected  to  put  the  name  of  the  patient  on 
the  label,  but  unfortunately  does  not  always  do  so.  It  is  im- 
portant if  there  is  more  than  one  patient  in  the  family.  The 
name  is  also  a  check  on  the  pharmacist,  in  case  he  should  send 
the  wrong  bottle. 

2.  The  symbol  ^  (pronounced  R  X,  but  always  written  as  a 
capital  R  with  the  tail  crossed).     This  is  placed  at  the  upper 
left-hand  corner  preceding  the  names  of  the  ingredients.     It  is 
used  at  present  as  an  abbreviation  of  the  Latin  word  "Recipe," 
the  imperative  of  the  verb  recipio,  I  take.     It  means,  therefore, 
"Take  thou, "  and  is  always  followed  by  the  accusative  case. 

3.  The  name  and  quantity  of  each  ingredient.     The  quantity 
may  be  a  weight,  a  measure,  or  a  number. 

4.  Directions    for    compounding — whether    the    pharmacist 
shall  simply  mix  the  ingredients  (M.  or  Misce),  or  make  them 
into  an  emulsion,  or  into  pills,  or  capsules,  or  a  plaster,  etc. 

5.  Directions  for  the  label — to  be  placed  there  by  the  phar- 
macist.    These  are  always  preceded  by  the  term  S.  or  Sig., 
which  is  an  abbreviation  of  the  Latin  imperative  signa,  meaning 
write  or  label. 

6.  The  physician's  signature. 

LIQUID  PRESCRIPTIONS 

Liquid  medicines  for  internal  use  are  administered  by  measure 
only,  hence  it  is  the  custom  to  make  the  total  quantity  of  the 
prescription  such  that  its  dose  will  be  a  teaspoonful,  a  dessert- 
spoonful, or  a  tablespoonful,  regardless  of  the  amount  of  active 
ingredients  present.  The  difference  between  the  measure  of  the 
active  ingredients  and  the  measure  of  the  dose  is  made  up  by 
the  vehicle.  It  is  for  this  reason  that  in  this  country  we  measure 
liquids  instead  of  weighing  them,  and  vary  the  amount  of  the 
vehicle  or  diluent  as  needed  to  make  the  total  the  number  of 
readily  measured  doses  desired.  Thus  of  the  vehicle  we  employ 
"q.  s.  ad  5iv,"  i.  e.,  as  much  as  may  be  sufficient  for  four  ounces 
(or  whatever  total  quantity  is  desired) ,  regardless  of  the  amount 
of  active  ingredients  present. 

The  necessity  for  this  may  be  illustrated  by  the  following 
prescription.  If  we  wish  to  give  10  minims  of  the  tincture  of 
nux  vomica  at  each  dose  in  the  following  bitter  appetizer  and 
tonic  mixture,  we  should  write: 

t^      Tinct.  nucis  vomicse 5ss 

Tinct.  cardamomi  comp q.  s.  ad  oiij 

M.  et  Sig. — One  dram  in  water  t.  i.  d.  a.  c. 


584  PHARMACOLOGY  AND   THERAPEUTICS 

This  calls  for  24  doses,  containing  240  minims  of  the  tincture 
of  mix  vomica,  i.  e.,  each  dose  contains  10  minims.  If  this 
should  be  written: 

]$      Tinct.  nucis  vomicae 5ss 

Tinct.  cardamomi  comp 5  iij 

the  total  quantity  of  the  prescription  would  be  Siiiss,  or  28  doses, 
and  each  dose  of  the  tincture  of  mix  would  be  8f  minims. 
Another  reason  for  avoiding  this  last  type  of  prescription  is  that 
the  quantities  make  an  irregular  total,  and  do  not  fit  any  standard 
sized  bottle. 

Measures. — The  measures  used  by  patients  are:  drop, 
teaspoon,  dessertspoon,  tablespoon,  sherry  glass,  wineglass, 
tea-cup,  and  glass  or  tumbler. 

Drops. — Drops  are  uncertain  measures,  their  size  differing 
according  to  the  viscosity  of  the  liquid,  the  temperature,  the 
fulness  of  the  container,  the  surface  from  which  dropped,  the 
rapidity  of  dropping,  etc.  Drop  bottles  and  medicine-droppers 
or  pipets  may  be  had,  but  these  vary  greatly  in  the  size  of  their 
orifices,  and  consequently  in  the  size  of  their  drops.  For  ex- 
ample, with  five  medicine-droppers  bought  at  different  drug- 
stores by  the  writer,  60  minims  of  the  tincture  of  nux  vomica 
required  respectively  200, 172, 167, 142,  and  132  drops,  while  from 
the  shop  bottle  containing  the  tincture  it  took  125  drops.  Of 
commercial  droppers,  the  only  one  that  we  know  that  is  made 
with  a  standard  orifice  is  the  Barnes  Medicine  Dropper  (not  the 
Barnes  Eye  Dropper).  With  this  dropper  60  drops  of  water 
measure  60  minims;  of  other  liquids  the  number  of  drops  varies 
according  to  their  nature.  The  drop  is,  therefore,  not  a  certain 
measure.  We  have  several  times  prescribed  the  Barnes  Medi- 
cine Dropper  and  found  that  the  druggist  sent  instead  a  dropper 
with  a  much  smaller  orifice. 

Approximately,  when  dropped  from  the  mouth  of  a  bottle, 
aqueous  liquids,  glycerin,  and  the  fixed  oils  measure  one  drop  to 
the  minim,  volatile  oils  and  strongly  alcoholic  liquids  2  drops  to 
the  minim,  ether  3  or  4  drops,  chloroform  5  drops,  and  bromoform 
6  drops. 

The  term  minim  should  not  be  used  in  the  directions  for  the 
patient  unless  the  patient  or  nurse  has  a  minim  glass  for  accurate 
measuring. 

Spoonfuls. — A  medicinal  teaspoonful  is  i  dram,  a  dessertspoon- 
ful is  2  drams,  a  tablespoonful  is  4  drams;  but,  unfortunately,  the 
spoons  in  common  use  are  not  made  to  standard,  and  hold  from 
25  to  50  per  cent,  more  than  these  amounts.  Hence  if  accuracy 
is  important,  it  is  a  good  plan  to  advise  the  use  of  measuring- 


VEHICLES   AND    FLAVORS  585 

glasses,  which  may  be  had  at  trifling  cost  correctly  graduated  on 
the  scale  of  one  dram  to  one  teaspoonful.  In  lieu  of  the  measur- 
ing-glass, DeLorme  suggests  that  we  reckon  on  six  teaspoonfuls 
to  an  ounce;  and  he  shows  how  much  such  a  procedure  tends  to 
simplify  the  calculation  of  quantities  in  prescriptions.  (See 
below.) 

Glassfuls. — A  sherry  glass  holds  about  2  ounces,  a  wineglass 
about  3  ounces,  a  glass  or  tumbler  about  8  ounces.  A  tea-cup 
holds  5  or  6  ounces. 

ADMINISTRATION  OF  LIQUIDS 
VEHICLES  AND  FLAVORS 

The  vehicle  is  the  diluent  or  solvent.  It  is  generally  em- 
ployed in  sufficient  quantity  to  make  the  dose  a  readily  measur- 
able amount.  A  vehicle  maybe — (a)  non-medicinal,  as  plain  water, 
or  a  flavored  liquid,  or  a  mucilaginous  liquid  to  hold  heavy  pow- 
ders in  suspension;  or  (b)  it  may  have  medicinal  value.  It  is  to 
be  remembered  that  a  prescription  is  often  rendered  more  palat- 
able and  no  less  efficient  through  the  medium  of  a  pleasant  tast- 
ing vehicle  or  an  added  flavor.  The  simple  vehicles  in  common 
use  are:  water,  the  flavored  waters  (anise,  cinnamon,  pepper- 
mint, wintergreen,  etc.),  alcohol,  sherry  wine,  aromatic  elixir, 
elixir  adjuvans  (incompatible  with  acids),  and  the  flavored 
syrups  (citric  acid,  almond,  ginger,  wild  cherry,  orange-peel, 
orange-flowers,  raspberry,  rose,  tolu,  and  the  compound  syrup 
of  sarsaparilla  which  contains  sarsaparilla,  licorice,  senna,  sassa- 
fras, anise,  and  wintergreen). 

Flavors. — Small  amounts  of  special  flavoring  substances,  with 
or  without  medicinal  properties,  are  frequently  added  to  prescrip- 
tions, especially  where  the  vehicle  is  plain  water  or  alcohol.  Such 
are:  (a)  Sweetening  agents,  as  sugar,  glycerin,  and  the  various 
syrups.  In  diabetes,  saccharin,  which  dissolves  in  alkaline  media, 
may  be  employed. 

(b)  Aromatics — the  waters  and  spirits  (bitter  almond,  anise, 
compound  spirit  of  orange,  cinnamon,  lavender,  peppermint, 
spearmint,  and  wintergreen),  the  elixirs,  the  fluidextract  of 
licorice  (incompatible  with  acids),  the  aromatic  fluidextract 
(made  of  cardamom,  ginger,  cinnamon,  and  nutmeg),  the  tinc- 
tures of  cardamom,  cinnamon,  ginger,  lemon-peel,  bitter  orange, 
sweet  orange,  tolu,  vanilla,  the  compound  tincture  of  cardamom 
(made  of  cardamom,  cinnamon,  and  caraway),  and  the  compound 
tincture  of  lavender  (made  of  lavender,  rosemary,  cloves,  cin- 
namon, and  nutmeg).  Many  of  the  flavored  syrups  combine 
sweetening  and  aromatic  properties. 


PHARMACOLOGY   AND   THERAPEUTICS 

Bitter  or  unpleasant  tastes  in  liquids  may  be  overcome  or 
partly  so  by  these  flavoring  substances  or  by  flavored  vehicles. 
Bitterness  may  be  especially  overcome  by  the  syrup  of  yerba 
santa.  (See  Part  II.)  Bitter  or  disagreeable  solids  are  sometimes 
made  up  into  flavored  liquid  mixtures. 

Colors  are  sometimes  added  to  watery-looking  liquids  for 
their  psychic  effect.  The  preparation  seems  more  like  "real 
medicine,"  and  if  it  is  a  powerful  remedy,  is  less  likely  to  be 
mistaken  for  something  harmless.  Colored  aromatic  tinctures, 
like  the  compound  tincture  of  lavender,  may  be  employed,  or 
tincture  of  persio,  or  carmine  (in  aqueous  liquid). 

(For  definitions  of  the  classes  of  liquids  employed,  see  Part  I.) 

ADMINISTRATION  OF  SOLIDS 

The  regular  diluent  for  powdered  drugs  dispensed  in  very 
small  quantities  is  sugar  of  milk.  Of  drugs  in  tablet  form,  the 
tablet  triturates  are  made  with  sugar  of  milk,  hypodermatic 
tablets  with  cane-sugar,  and  compressed  tablets  without  any 
diluent  except  in  a  few  cases  where  it  is  necessary  to  increase 
the  cohesive  properties  of  the  powder. 

For  pills,  the  ingredients  must  be  worked  together  into  a 
mass,  which  is  then  divided  equally  into  the  requisite  number  of 
parts.  These  parts  are  then  given  a  round  or  elliptic  shape. 
The  pills  must  be  plastic,  to  permit  their  shaping,  but  they  must 
be  firm  enough  to  retain  their  shape  on  standing. 

An  excipient  is  a  substance  employed  to  give  proper  con- 
sistence to  a  mass.  It  may  be  water,  glycerin,  glucose,  syrup, 
glycerite  of  starch,  extract  of  gentian,  etc.  The  choice  of  excipi- 
ent should  be  left  to  the  pharmacist.  For  oxidizing  substances, 
as  silver  nitrate  or  potassium  permanganate,  the  diluent  should 
be  an  inert  powder,  such  as  kaolin,  and  the  excipient  an  inert 
substance,  like  petrolatum. 

Pills  may  be  rolled  in  some  powder,  such  as  starch  or  lyco- 
podium,  to  prevent  their  sticking  together,  or  they  may  have 
a  special  coating.  The  more  common  coatings  are  gelatin,  sugar, 
and  silver.  Pills  intended  to  pass  through  the  stomach  un- 
changed, but  to  disintegrate  in  the  intestine,  are  known  as 
" enteric"  pills,  and  are  usually  coated  with  salol  or  keratin. 
These  coatings  are  insoluble  in  the  acid  gastric  juice,  but  dis- 
solve in  the  alkaline  intestinal  contents.  The  so-called  chocolate- 
coated  pills  are  really  only  gelatin  or  sugar-coated  pills  with 
chocolate  color.  The  objects  in  coating  pills  are:  to  improve 
their  appearance,  to  improve  their  keeping  qualities,  to  hide 
their  taste,  or  to  make  them  "enteric." 

To  hide  a  bitter  or  unpleasant  taste,  powders  may  be  dis- 


LATIN  587 

pensed  in  liquid  form  with  syrup  or  other  flavoring  material,  or 
may  be  made  into  capsules,  cachets,  or  coated  pills.  Drugs  of 
sticky  consistence,  such  as  extracts,  may  be  made  into  a  mass, 
divided  into  the  requisite  number  of  parts,  and  then  put  into 
capsules. 

Tablet  triturates  have  sugar  of  milk  as  a  basis,  and  their 
solubility  or  power  of  disintegration  depends  on  that  of  the  sugar 
of  milk.  They  can,  therefore,  be  swallowed  whole  without  fear 
of  non-disintegration.  They  are  best  suited  for  those  metallic 
and  alkaloidal  salts  of  which  the  dose  is  very  small.  Extracts 
and  other  vegetable  materials  should  be  used  in  tablet  triturates 
only  in  very  minute  quantity.  Tablet  triturates  for  diabetics 
may  be  made  with  some  non-carbohydrate.  Hypodermic  tablets 
are  usually  made  with  cane-sugar  to  insure  ready  solubility, 
but  they  readily  become  broken  on  handling. 

Compressed  tablets  vary  in  hardness  according  to  the  degree 
of  compression  to  which  they  have  been  subjected,  and  in  solu- 
bility according  to  the  nature  of  the  drugs  of  which  they  are 
made.  Compressed  tablets  of  readily  soluble  substances,  as 
ammonium  chloride  or  potassium  iodide,  should  be  dissolved 
in  water  before  taking,  or  taken  with  a  copious  draft  of  water. 
If  made  of  substances  that  are  insoluble'or  soluble  with  difficulty, 
as  bismuth  subnitrate  or  phenacetin,  they  should  be  broken  up 
before  swallowing. 

(For  other  solids  see  Definitions,  Part  I.) 

LATIN 

The  names  of  the  ingredients  are  always  written  in  Latin, 
for  the  following  reasons: 

1.  Latin  is  a  universal  language,  so  is  readable  anywhere. 

2.  It  is  a  dead  language,  so  is  not  subject  to  change. 

3.  //  is  the  language  of  science,  so  is  explicit,  and  is  not  am- 
biguous.   In  the  names  of  plant-drugs,  for  example,  Aristolochia 
serpentaria    always  stands  for  the  same  plant  wherever  it  is 
grown,    while   its   English   synonym,    snakeroot,   is   applied   to 
different  plants  in  different  localities. 

4.  It  may  be  advisable  to  keep  from  the  patient  the  nature  of 
the  drug.     Patients  have  many  preconceptions  and  prejudices 
regarding  drugs.     One  patient   assures   the  doctor  that  he  is 
always  made  ill  by  calomel  or  phenacetin,  yet  obtains  great 
benefit  from  a  prescription  for  hydrargyri  chloridum  mite  or 
acetphenetidin.     Another  has  found  cascara  absolutely  useless 
for  his  constipation,  but  secures  a  comfortable  laxative  movement 
from  rhamnus  purshiana. 

Though    prescriptions    are    written    in    Latin,    prescription 


588  PHARMACOLOGY  AND   THERAPEUTICS 

writing  may  be  accomplished  with  very  little  knowledge  of  the 
language;  for  the  construction  follows  rules  that  are  not  always 
those  of  classic  Latin;  and  the  customary  methods  of  abbrevia- 
tion enable  one,  without  fear  of  criticism,  to  omit  a  Latin  ending 
if  the  correct  one  is  not  known.  Approved  prescription  writing, 
however,  requires  some  knowledge  of  Latin  and  a  familiarity  with 
certain  rules. 

The  following  information  about  Latin  words  is  not  given 
with  any  intent  to  teach  the  language,  but  solely  with  the  desire 
to  facilitate  prescription  writing  for  those  who  do  not  know 
Latin. 


NOUNS 

A  general  rule  for  case-endings  in  the  name  of  ingredients 
is:  The  name  of  the  substance  or  the  class  of  remedy  takes  the 
genitive  ending  when  the  quantity  is  a  weight  or  measure;  and  the 
accusative  ending  when  the  quantity  is  a  number. 

The  genitive  case  is  the  possessive,  implying  the  preposition 
"of."  For  example,  1^  Syrupi  scillse  compositi,  5ij,  may  be 
translated  literally  "Take  (thou)  2  ounces  of  the  compound 
syrup  of  squill."  1^  Acetanilidi,  gr.  xxx,  is  "Take  30  grains  of 
acetanilid."  The  object  of  the  verb  "recipe"  in  these  cases  is 
the  word  for  ounces  (uncias)  or  grains  (grana),  the  plural  accusa- 
tive. 

The  accusative  case  represents  the  object  of  a  verb.  When  the 
quantity  is  a  number,  this  number  is  a  numeral  adjective;  and 
the  object  of  the  verb  recipe  is  the  name  of  the  numbered  objects. 
For  example:  1^  Capsulas  acetphenetidini,  aa  gr.  v,  No.  xij— 
"Take  12  capsules  of  phenacetin,  each  of  5  grains."  That  is, 
"Capsulas"  is  the  object  of  the  verb  recipe.  The  term  No. 
(numero)  is  customarily  placed  before  numbers  of  this  kind. 
It  may  be  translated  "in  number."  Thus  the  prescription 
might  be  read:  "Take  capsules  of  phenacetin,  each  of  5  grains, 
and  in  number,  12."  The  genitive  singular  ending  is  the  one 
most  required,  and  this,  with  the  accusative  singular  and  plural, 
are  all  that  need  be  learned.  The  case-endings  of  nouns  used  in 
prescriptions  are: 

SINGULAR  PLURAL 

Gen.  Ace.  Ace. 

1.  Of  nouns  ending  in  a  (fern.),  as  quinina.  ...       ae  am  as 

2.  Of  nouns  ending  in  us  (masc.),  as  strophan- 

thus i  um  os 

3.  Of  nouns  ending  in  um  (neuter),  as  chlo- 

ralum i  um  a 

4.  Almost  all  other  nouns is  em         es  (masc.) 

es  (fern.) 
a  (neuter) 


ADJECTIVES 


589 


Of  this  last  class,  most,  but  not  all,  have  a  connecting  link, 
d,  t,  r,  etc.,  between  the  root  of  the  word  and  the  ending. 

Examples  giving  the  nominative  and  genitive  endings  are: 


With  the  nominative  ending 

In  is:     Cannabis,  cannabis. 

Digitalis,  digitalis. 

Hamamelis,  hamamelidis. 

Pulvis,  pulveris. 

Arsenis,  arsenitis. 
In  as:    Nitras,  nitratis. 

Sulphas,  sulphatis. 

Asclepias,  asclepiadis. 

Mas,  mans. 
In  ma:  Magma,  magmatis. 

Theobroma,  theobromatis. 

Physostigma,  physostigmatis. 
In  c:      Lac,  lactis. 
In  I:      jEthyl,  aethylis. 

Alcohol,  alcoholis. 

Mel,  mellis. 
In  n:     Limon,  limonis. 

Semen,  seminis. 

Erigeron,  erigerontis. 


In  o:      Solutio,  solutionis. 

Mucilago,  mucilaginis. 

Pepo,  peponis. 

Sapo,  saponis. 
In  r:      Liquor,  liquoris. 

/Ether,  aetheris. 

Zingiber,  zingiberis. 
In  s:      Adeps,  adipis. 

Pars,  partis. 

Flos,  Boris. 

Juglans,  juglandis. 
In  x:      Borax,  boracis. 

Rumex,  rumicis. 

Filix,  filicis. 

Calx,  calcis. 

Nux,  nuris. 


Exceptions  to  Rule  i  are  those  ending  in  ma,  us,  theobroma, 
theobromatis;  physostigma,  physostigmatis. 

Exceptions  to  Rule  2  are  five  in  number,  as  follows:  Rhus, 
rhois;  cornus,  cornus;  fructus,  fructus;  quercus,  quercus;  spiritus, 
spiritus. 

Of  aloe  (fern.)  the  genitive  is  aloes,  the  accusative,  aloen. 
Of  eriodictyon  the  genitive  is  eriodictyi;  of  toxicodendron, 
toxicodendri.  Dies  and  res  are  employed  in  the  ablative  case 
only,  as:  ter  in  die;  pro  re  nata. 

Indeclinable  nouns,  i.  e.,  those  having  the  same  ending  in  all 
cases,  are:  azedarach,  gambir,  jaborandi,  sassafras;  and  most 
nouns  ending  in  u,  and  some  in  o,  as  buchu,  catechu,  condurango, 
cusso,  kino,  matico.  Some  which  are  declinable,  but  which 
have  no  change  in  the  genitive,  are:  berberis,  cannabis,  digitalis, 
hydrastis,  sinapis;  cornus,  fructus,  quercus,  spiritus. 

ADJECTIVES 

Adjectives  agree  in  number,  gender,  and  case  with  the  noun 
which  they  modify,  (a)  Those  ending  in  us  (masculine),  a 
(feminine),  urn  (neuter),  are  of  the  second  declension,  and  take 
the  same  case-endings  as  nouns  with  the  same  terminals,  as  in 
Rules  i,  2,  and  3.  The  most  employed  are:  albus  (white), 
amarus  (bitter),  aromaticus  (aromatic),  benzoinatus  (benzoin- 
ated),  camphoratus  (camphorated),  catharticus  (cathartic), 
colatus  (strained),  compositus  (compound),  corrosivus  (cor- 


59°  PHARMACOLOGY   AND   THERAPEUTICS 

rosive),  dilutus  (diluted),  durus  (hard),  exsiccatus  (dried), 
flavus  (yellow),  fluidus  (fluid),  frigidus  (cold),  granulatus  (granu- 
lated), hydratus  (hydrated),  inspissatus  (inspissated),  magnus 
(great),  parvus  (small),  ponderosus  (heavy),  praecipitatus  (pre- 
cipitated), prasparatus  (prepared),  purificatus  (purified),  recti- 
ficatus  (rectified),  reductus  (reduced),  rubrus  (red),  saturatus 
(saturated),  tepidus  (warm),  unus  (one).  Duo  (two)  has 
accusative  duos. 

Examples  of  agreement  with  the  noun  are :  syrupus  aromati- 
cus,  fluidextractum  aromaticum,  cochlearia  parva,  pilulas  cathar- 
ticas,  tinctura  lavandulas  composita,  pulveris  glycyrrhizae  com- 
positi. 

(b)  Those  ending  in  is  (masculine  and  feminine),  e  (neuter), 
take  endings  as  follows: 

is  takes  gen.  is,  ace.  em,  ace.  plural  es. 

e  takes  gen.  is,  ace.  e,  ace.  plural  ia. 

Examples  are:  aequalis  (equal),  animalis  (animal),  dulcis 
(sweet),  fortis  (strong),  glacialis  (glacial),  levis  (light),  mitis 
(mild),  mollis  (soft),  omnis  (every),  simplex,  icis  (simple), 
solubilis  (soluble),  talis  (such),  tres  (three),  vegetabilis  (vege- 
table), viridis  (green).  Some  ending  in  ens  have  genitive  entis, 
and  ace.  entem  or  ente,  as  adstringens  (astringent),  bulliens 
(boiling) ,  effervescens  (effervescing) ,  f ervens  (hot) ,  recens  (fresh) . 

Examples  of  agreement  with  the  noun  are:  succi  limonis 
recentis,  partes  aequales,  amygdalae  dulcis,  hydrargyri  chJoridum 
mite,  doses  tales. 

Adjectives  of  one  declension  may  modify  nouns  of  another 
declension,  but  each  takes  the  ending  of  its  own  declension. 

OTHER  WORDS 

Besides  nouns  and  adjectives,  there  are  employed  in  the 
directions  for  the  pharmacist  and  for  the  label  a  few  special 
words  that  should  be  known.  They  are : 

1.  Verbs — adde  (add),  bulliat,  bulliant  (let  it  or  them  boil), 
cola  (strain),  coletur  (let  it  be  strained),  detur,  dentur  (let  it  or 
them  be  given),  divide  (divide),  extende  supra  (spread  upon), 
fiat,  fiant  (let  it  be,  let  them  be),  filtra  (filter),  misce  (mix), 
mitte  (send),  pone  (place),  signa  (write),  solve  (dissolve),  tere 
(rub  in  a  mortar;  triturate). 

2.  Adverbs — bene  (well),  statim  (immediately;  at  once). 

3.  Prepositions — (a)  ad  (for;  up  to),  ante  (before),  in  (into), 
supra  (upon),  post  (after) ,  govern  the  accusative.    After  a  transi- 
tive verb  in  governs  the  accusative  and  expresses  the  English 
into,  as  "divide  in  capsulas"  (divide  into  capsules).     After  an 


THE   FORM   OF   A   PRESCRIPTION  59! 

intransitive  verb,  in  takes  the  ablative,  and  is  equivalent  to 
the  English  in,  as  "in  aqua"  (in  water). 

(6)  cum  (with),  pro  (for;  according  to),  sine  (without),  in 
(in),  govern  the  ablative. 

(c)  Ana  (each  of;  of  each)  governs  the  genitive. 

4.  Conjunctions — aut  (or),  et  (and),  vel  (or). 


THE   FORM    OF  A   PRESCRIPTION 

Almost  all  prescriptions  are  of  two  classes,  viz. :  I.  Material 
to  be  sent  in  bulk,  as  liquids,  ointments,  mixtures  of  powders, 
etc.  II.  Objects  to  be  counted,  as  pills,  tablets,  powders,  etc. 
Hence,  it  is  easy  to  learn  one  or  two  forms  for  each  of  these 
classes.  Prescriptions  are  spoken  of  as  simple  when  they  con- 
tain but  one  preparation,  and  compound  when  they  include  more 
than  one.  The  following  types  represent  variations  in  the  two 
classes : 

1.  Material  Dispensed  in  Bulk. — i.  Simple   Prescriptions.— 

1^     Linimenti  chloroformi 5  ij 

Sig. — Rub  well  over  shoulder  every  four  hours. 

1^     Pulveris  glycyrrhizse  compositi 5j 

Sig. — Take  a  level  teaspoonful  in  water  each  night. 

1$    Unguenti  hydrargyri  oxidi  flavi 5ss 

Sig. — Rub  into  eyelids  morning  and  night. 

2.  Compound    Prescriptions. — (a)  Where    special    directions 
to  the  pharmacist  would  be  superfluous,  i.  e.,  where  no  possible 
method  of  mixing  according  to  the  pharmacist's  art  could  make 
anything  other  than  that  desired.    In  such  a  case  the  directions 
for  compounding  are  limited  to  M.  or  Misce,  and  it  is  a  super- 
fluity to  write  M.  et  ft.  mistura,  M.  et  ft.  unguentum,  M.  et 
ft.  collyrium  (eye-wash),  etc.    Examples  are: 

1^      Sodii  bicarbonatis oj 

Fluidextracti  rhamni  purshianse 5ij 

Mistura  rhei  et  soda? q.  s.  ad  3irj 

M.  et  Sig. —  5ij  in  water  t.  i.  d.  2  h.  p.  c. 

J$     Sulphuris  pracipitati oij 

Olei  cadini 5iss 

Unguenti  zinci  oxidi q.  s.  ad  §j 

M.  Sig. — Apply  to  itching  area  twice  a  day. 
ty    Magnesii  oxidi oij 

Sodii  chloridi 5  j 

Sodii  bicarbonatis 3  ss 

M.   et  Sig. — One  level  teaspoon  in  half  a  glass  of  hot  water  half  an  hour 

before  breakfast. 

(b}  Where  special  directions  to  the  pharmacist  are  necessary 
or  serve  to  avoid  uncertainty.  Such  a  necessity  is  only  occasional. 


592          PHARMACOLOGY  AND  THERAPEUTICS 

Ifr      Buchu 3iv 

Matico 3ij 

Aquae q.  s.  ad  5  viij 

Ft.  infusum. 

Sig. —  3ij  in  a  wineglass  of  water  every  four  hours. 

In  special  cases  directions  for  compounding  may  be  placed 
after  a  portion  of  the  ingredients,  as: 

1$      Peponis 3ij 

Granati, 

Cusso aa  3  i 

Aquae  bullientis q.  s.  ad  5  vj 

Ft.  infusum,  cola  et  adde — 

Oleoresinae  aspidii 3] 

Mucilaginis  acaciae 5  ss 

Aquae q.  s.  ad  3  viij 

Sig. — Take  half  statim  and  half  in  three  hours. 

n.    Objects  to  be  Counted. — i.  Commonly  Kept  Ready-made — 
(a)  With  standard  name,  or  with  only  one  ingredient: 

T^     Pilulas  catharticas  compositas No.  iij 

Sig. — Take  at  bedtime. 

1$    Capsulas  quininae  sulphatis,  gr.  v No.  xij 

Sig. — One  t.  i.  d.  p.  c. 

(5)  With  no  standard  name — 

!$     Olei  ricini njjiiss 

Salolis gr.  iiss 

M.  et  ft.  capsula  No.  j.  Mitte  tales  No.  xx. 
Sig. — One  q.  4  h. 

(This  omission  of  multiplication  should  never  be  resorted  to 
except  for  ready-made  objects.   It  would  suggest  a  lazy  physician.) 
2.  To  Be  Made  Up  Extemporaneously — 

1^     Acetanilidi gr.  xxx 

Ft.  chartse  No.  vj. 

Sig. — One  q.  3  h. 

J£     Strychnine  sulphatis gr.  l/$ 

Acetphenetidini gr.  xxiv 

Acetanilidi gr.  xvj 

M.  et  ft.  capsulae  No.  viij.     (Or  M.  et  ft.  in  capsulas  No.  viij.) 
1^     Aloes  purificataj gr.  xviij 

Massae  hydrargyri 3ss 

Olei  menthos  piperitac gtt.  iij 

M.  et  ft.  pilulaa  No.  xij.     (Or  M.  et  ft.  in  pilulas  No.  xij.) 
Sig. — Two  at  bedtime  once  a  week. 


The  first  example  of  this  section  may  also  be  written — 

I^     Chartas  acetanilidi  gr.  v  (or  "aa  gr.  v") .  .No.  vj. 
Sig. — One  q.  3  h. 

The  accusative  plural  forms  of  the  names  of  objects  to  be 


FIGURING   THE    QUANTITIES  593 

counted  are:  cachetas  (cachets),  capsulas  (capsules),  chartas 
or  chartulas  (powders),  pilulas  (pills),  suppositoria  (supposi- 
tories), tabellas  (tablets),  tabellas  trituratas  (tablet  triturates), 
tabellas  hypodermaticas  (hypodermic  tablets),  trochiscos  (tro- 
chees) . 

If  it  is  desired  that  the  pharmacist  send  a  piece  of  apparatus 
for  the  administration  of  the  remedy,  such  as  a  camel's-hair 
pencil,  a  throat  brush,  an  eye-dropper,  a  medicine-dropper,  an 
eye-cup,  this  may  be  indicated  by  writing  the  name  on  the  lower 
left-hand  corner  of  the  prescription  blank.  Thus: 

1^    Sol.  sat.  acidi  borici 5  j 

Sig. — Warm  and  use  in  eye-cup  every  three  hours. 

W.  M.  JOHNSON. 
One  eye-cup. 

FIGURING  THE  QUANTITIES 

To  acquire  careful  habits  it  is  wise,  in  writing  a  compound 
prescription,  to  put  down  the  names  of  all  the  ingredients  desired 
before  inserting  the  quantities.  Then  multiply  the  number  of 
doses  by  the  desired  dose,  and  set  down  the  result  opposite  the 
name  of  the  ingredient.  Total  quantities  are  usually  expressed 
in  the  nearest  half  or  whole  number  rather  than  in  fractional 
amounts,  the  error  in  such  a  case  being  small  in  proportion  to 
the  whole  amount  of  the  dose. 

In  a  liquid  prescription  the  name  of  the  vehicle  always  comes 
last,  followed  by  q.  j.  ad  and  the  total  quantity  of  the  prescrip- 
tion. 

A  number  of  ways  to  promote  ease  in  the  calculations  have 
been  suggested.  A  one-ounce  mixture  may  be  reckoned  as  eight 
teaspoonful  doses,  a  two-ounce  as  15  teaspoonfuls,  a  three-ounce 
as  24  teaspoonfuls,  and  a  four-ounce  as  30  teaspoonfuls. 

Hence  a  two-ounce  bottle  contains  15  or  16  teaspoonfuls;  a 
four-ounce  bottle  contains  15  or  16  dessertspoonfuls;  an  eight- 
ounce  bottle  contains  15  or  1 6  tablespoonfuls. 

One  simple  rule  is:  For  an  eight-ounce  mixture  with  tea- 
spoonful  dose  prescribe  as  many  drams  of  the  ingredient  as 
you  desire  minims  or  grains  at  a  dose;  for  a  four-ounce  mixture, 
half  as  many  drams;  for  a  three-ounce  mixture,  two-fifths  as 
many,  and  for  a  two-ounce  mixture,  one-fourth  as  many.  In 
other  words,  in  a  two-ounce  mixture  with  teaspoonful  dose  one 
dram  of  the  substance  gives  a  4-grain  or  minim  dose;  in  a  three- 
ounce  mixture  one  dram  gives  a  2^-grain  or  minim  dose;  in  a 
four-ounce  mixture  one  dram  gives  a  2-grain  or  minim  dose. 

Example :  The  single  dose  of  the  prescription  being — 

38 


594          PHARMACOLOGY  AND  THERAPEUTICS 

1^     Ammonii  chloridi gr.  v 

Syrupi  ipecacuanhae njjviij 

Aquae q.  s.  ad  5  j 

z-OuNCE  MIXTURE  3-OuNCE  MIXTURE    4-OuNCE  MIXTURE 

T.%  drams gr.  Ixxv  5ij  oiiss 

2      drams 5ij  oiij  oiv 

to  2  ounces ad  5ij  ad  5iij  ad  5iv 

Observe  that  increase  in  size  of  mixture  requires  increase 
in  amount  of  active  ingredients.  Increase  in  dose  of  mixture 
requires  decrease  in  amount  of  active  ingredients. 

Where  the  ordinary  spoons  are  to  be  used  and  not  a  measur- 
ing-glass, a  method  recommended  by  De  Lorme  is  to  assume 
six  teaspoonfuls  to  an  ounce  and  follow  this  rule:  "Employ  ;/2' 
dram  to  each  ounce  for  five-grain  or  five-minim  doses  in  each 
teaspoonful. "  This  does  not  apply  to  preparations  for  external 
use,  i.  e.,  those  not  measured  by  the  spoon. 

There  is  a  method  advocated  by  some,  of  figuring  out  the 
doses  in  the  English  system,  but  writing  the  prescription  accord- 
ing to  the  metric  system.  The  rule  is  to  write  always  for  sixteen 
doses,  i.  e.,  a  two-ounce  mixture  (written  60  c.c.)  if  the  dose  is  a 
teaspoonful,  a  four-ounce  mixture  (written  120  c.c.)  if  the  dose 
is  a  dessertspoonful,  an  eight-ounce  mixture  (written  240  c.c.) 
if  the  dose  is  a  tablespoonful.  Then  put  down  for  each  ingredient 
as  many  grams  or  cubic  centimeters  as  you  desire  grains  or 
minims  per  dose.  The  above  prescription  by  this  method  would 
read— 

T^     Ammonii  chloridi 5.0 

Syrupi  ipecacuanhse 8.0 

Aqua; q.  s.  ad  60.0 

Sixteen  powders  or  pills  or  capsules  may  be  prescribed  in 
the  same  way;  eight  powders  would  require  half  as  many  grams 
as  grains  per  dose,  etc.  This  is  an  easy  method  for  older  doctors 
who  know  their  doses  in  the  English  system,  and  desire  to  make 
their  prescriptions  conform  with  the  metric  system.  But  as  it 
requires  thinking  of  doses  in  grains  and  minims,  and  yet  writing 
in  metric  amounts,  it  is  an  unwise  method  for  a  student  to  learn. 
If  he  is  going  to  write  metric  prescriptions,  he  had  better  learn 
his  doses  at  the  outset  in  the  metric  system. 

In  prescriptions  for  children  a  simple  application  of  the 
author's  age-weight  rule  for  dosage  (see  Part  I)  is  to  make  the 
prescription  for  two  ounces  with  teaspoonful  dose,  and  to  put 
down  for  each  ingredient  half  as  many  grains  or  minims  as  its 
adult  dose,  multiplied  by  the  age  of  the  patient  plus  5.  Thus,  for 
a  child  of  two  years  the  prescription  above  would  read: 


FIGURING   THE    QUANTITIES  595 

1$     Ammonii  chloridi gr.  xij 

Syrupi  ipecacuanha? TTJJXX 

Aquae q.  s.  ad  5U 

If  using  Cowling's  rule,  the  prescription  may  be  a'three-ounce 
mixture  with  teaspoonful  dose,  i.  e.,  24  doses.  Then  the  adult 
dose  multiplied  by  the  age  at  next  birthday  will  be  the  total 
amount.  For  a  child  of  two  it  would  read: 

1$     Ammonii  chloridi gr.  xv 

Syrupi  ipecacuanha? njjxxiv 

Aquae q.  s.  ad  §  ii j 

For  1 2  doses  it  would  read  half  these  amounts. 

"Lazy  Man"  Prescriptions. — The  method  of  writing  bulk 
prescriptions,  by  putting  down  the  single  dose  of  each  ingredient 
and  directing  the  pharmacist  to  send  a  certain  number  of  such 
doses  (mitte  tales  doses),  is  known  as  the  ''lazy  man's  method," 
and  is  not  approved.  Such  a  method  is  good  usage  only  in  pre- 
scriptions for  objects  of  standard  formula,  such  as  pills,  capsules, 
etc.,  which  are  understood  to  be  kept  ready  made  by  the  phar- 
macist. (See  Types  of  Prescriptions.) 

A  shot-gun  prescription  is  one  that  contains  a  number  of 
substances  which  have  no  essential  therapeutic  affinity.  It  is 
the  result  of  an  ignorant  attempt  to  hit  the  trouble,  no  matter 
what  may  be  its  nature.  Warburg's  tincture  is  a  good  example 
of  such. 

Good  Usage. — In  prescription  writing,  clearness  is  the  im- 
portant thing  and  Latin  is  the  medium  of  expression,  but  cer- 
tain forms  have  become  approved,  and  certain  modes  of  expres- 
sion are  accepted  as  the  best  custom.  The  following  precepts 
are  according  to  ''good  usage": 

1.  Each  ingredient  name  shall  have  a  separate  line. 

2.  Each  line  begins  with  a  capital  letter. 

3.  Ditto  marks  are  not  permissible. 

4.  The  names  of  the  most  active  ingredients  are  placed  first, 
the  names  of  flavors  and  correctives  afterward,  the  name  of  the 
diluent  last.     In  a  liquid  prescription  the  names  of  solids,  if  active 
medicinally,  before  those  of  liquids,  and  the  vehicle  last. 

5.  In  a  title  the  name  of  the  class  of  preparation    (as  pilula, 
tinctura,  elixir,  etc.)  comes  first;  a  modifying  adjective  usually 
last,  as  syrupi  sarsaparillae  compositi.     Of  salts,  the  name  of  the 
base  first,  as  sodii  bromidi;  of  acids,  the  term  for  acid  first,  as 
acidi  hydrochlorici. 

6.  Latin  is  regularly  employed  for  the  names  of  the  ingre- 
dients and  for  the  directions  for  compounding. 


596  PHARMACOLOGY  AND  THERAPEUTICS 

7.  In  the  directions  for  the  label,  Latin  is  employed  only  in 
certain   recognized    expressions,  hence  Latin  and    English    are 
mixed   indiscriminately.     The   pharmacist   writes   these   direc- 
tions on  the  label  in  English. 

8.  When  in  doubt  as  to  the  correct  Latin  expression,  write 
in  English;  when  uncertain  of  the  correct  Latin  ending,  omit  it. 
The  understanding  of  the  physician's  order  by  the  pharmacist 
is  of  more  importance  than  the  correctness  of  the  Latin.    Com- 
plicated Latin   constructions   add   the   risk   of  being   wrongly 
interpreted  by  the  pharmacist,  who  is  not  of  necessity  a  Latin 
scholar. 

9.  For  amounts  over  two  ounces  make  the  total  of  a  liquid 
prescription  conform  with  the  sizes  of  bottle  found  in  the  phar- 
macies; for  if  a  bottle  is  only  partly  filled,  the  patient  may  think 
that  some  of  the  medicine  has  been  spilled  or  an  error  made  by 
the  pharmacist.    The  vials  used  in  the  United  States  are:  1,2, 
and  4  dram,  i,  2,  3,  4,  6,  8,  12,  16,  and  32  ounce. 

10.  In  acute  illness  order  a  small  number  of  doses,  both  to 
permit  frequent  change  in  the  treatment  and  to  avoid  having 
the  medicine  outlast  the  sickness.    The  larger  amounts  may  be 
prescribed  if  the  dose  is  to  be  repeated  frequently,  or  if  the 
medicine  is  to  be  continued  definitely  without  change  for  a  long 
time. 

11.  When  writing  for  more  than  the  ordinary  dose  of  a 
potent  drug,  as  for  one  grain  of  morphine  sulphate  or  ^  grain 
of  strychnine  sulphate,  always  double  underline  the  quantity 
or  write  O.  K.  or  dose  correct,  otherwise  the  pharmacist  may  think 
it  an  error  and  refuse  to  dispense  the  prescription  till  the  doctor 
is   communicated   with.     Do   not   employ   exclamation   marks 
for  this  purpose,  for  these  have  been  mistaken  for  Roman  nume- 
rals.   Professor  Remington  reports  a  prescription  for  one  grain 
of  morphine  sulphate  to  be  divided  into  two  powders.     The 
physician  intended  to  write  1$      Morphinoesulphatis,  gr.  j  !! — the 
exclamation  marks  indicating  that  he  intended  the  large  dose. 
But  he  did  actually  write  1^    Morphinae  sulphatis,  gr.  jjj,  the 
exclamation  marks  being  turned  upside  down. 

12.  When  the  formula  or  name  of  the  medicine  is  desired 
on  the  label  the  term  "Label,"  "1}  on  label,"  "Formula  on 
label,"  may  replace  or  be  added  to  other  directions  for  the  label. 
Examples  are:  "Sig.- — Label,"  or  "Sig. — Take  three  times  a  day — 
Formula  on  label." 

13.  The  terms  "For  external  use"  and  "Shake  before  using" 
need  not  be  specified  in  the  directions,  for,  when  the  nature  of  the 
preparation  indicates  it,  these  are  regularly  placed  upon  the 
bottle  by  the  pharmacist.     But,  unless  the  physician  so  directs, 


ABBREVIATIONS  597 

the  term  " Poison!"  is  never  placed  upon  a  prescription  for 
internal  use,  as  for  strychnine  tablets  or  Fowler's  solution.  And 
it  is  often  omitted  from  poisonous  preparations  for  external  use, 
as  belladonna  liniment. 

14.  The  letters  P.  P.  following  a  patient's  name  stand  for 
"poor  patient,"   and  secure  from  the  pharmacist  his  lowest 
price.    The  expressions  "ne  repetatur, "  or  "not  to  be  repeated," 
and  "give  no  copy,"  are  regularly  heeded  by  the  pharmacist. 

15.  The  use  of  the  term  "as  directed"  or  "use  as  directed" 
as  the  sole  direction  for  the  patient  should  be  avoided  if  possible, 
for  it  does  not  indicate  to  the  druggist  how  or  in  what  dose  the 
remedy  is  to  be  employed.    The  physician  thus  lacks  the  phar- 
macist's valuable  check  upon  the  prescription.    If  for  esthetic 
or  other  reasons  it  is  desired  to  omit  the  directions,  as  for  douches, 
injections,  etc.,  they  should  be  given  to  the  patient  in  writing; 
for  patients,  especially  those  who  are  nervous  or  quite  ill,  are 
prone  to  forget  verbal  directions,  or,  what  is  worse,  to  remember 
(!)  them  wrongly. 

1 6.  Where  there  can  be  no  possible  misinterpretation,  abbre- 
viation may  be  good  usage.     See  below. 

17.  Never  sign  a  prescription  or  let  it  get  out  of  your  hands 
without  first  reviewing  it.    Because  of  distraction  of  the  physi- 
cian's attention  by  anxious  or  talkative  friends,  or  for  other 
reasons,  errors  in  prescriptions  are  of  frequent  occurrence.    The 
most    common    error    is    omission    or    transposition    of    the 
amounts  of  the  ingredients.     For  example,  one  recently  seen 
by  the  writer  called  for  potassium  iodide,  gr.  j,  and  mercuric 
iodide,   5iij,  the  amounts  being  transposed. 

Note. — If  a  pharmacist  'phones  you  or  calls  upon  you  rela- 
tive to  the  interpretation  of  one  of  your  prescriptions,  do  not 
take  offense  as  if  it  were  an  insult  for  any  one  to  suppose  your 
handiwork  anything  less  than  perfect.  On  the  contrary,  be 
grateful  to  the  pharmacist;  for  he  will  protect  you  and  will  not 
tell  the  patient  of  your  error,  even  though  he  has  to  shoulder 
the  blame  himself  for  the  delay  in  the  dispensing  of  the  prescrip- 
tion. The  pharmacist  is  no  more  prone  than  other  people  to 
make  trouble  for  himself  unnecessarily,  and  if  he  questions  one 
of  your  prescriptions,  you  may  take  it  for  granted  that  he  has  a 
reason  for  his  action,  even  though  it  may  not  be  apparent  to  you. 

ABBREVIATIONS 

When  there  can  be  no  possible  mistake  in  meaning,  abbre- 
viations are  allowable  as  follows: 

I.  Of  Ingredients. — (a)  In  the  name  of  the  class  of  prepara- 
tions, as  elix.,  tinct.,  syr.,  pil.,  suppos.,  ungt.  (or  ung.).  The 


PHARMACOLOGY  AND  THERAPEUTICS 

abbreviation  Tr.  should  not  be  employed  for  tincture,  as  in 
script  form  it  has  frequently  been  incorrectly  read  Fe. — i.  e., 
fluidextract. 

(6)  In  modifying  adjectives,  as  aq.  for  aequalis,  comp.  for 
compositus,  ppt.  for  praecipitatus,  recent,  for  recentis,  sat.  for 
saturatus. 

(c)  In  amounts — q.  s.  for  quantum  sufficiat  (as  much  as  may 
be  required),  aa  for  ana  (of  each),  and  the  regular  symbols  of 
weights  and  measures. 

(d)  In  prepositions — c  for  cum,  s  for  sine. 

II.  In  the  Directions  for  Compounding. — (a)    In  nouns  and 
adjectives,  as  each.,  chart.,  pil.,  suppos.,  tab.,  tab.  trit.,  tab. 
hyp.,  troch.,  scat,  (scatulam  =  a  box),  dos.  tal.  (doses  tales  = 
such  doses). 

To  express  the  kind  of  coating  for  pills  write  argent,  (argenti- 
ferus)  =  silver-coated,  sacchar.  (sacchariferus)  =  sugar-coated, 
and  gelat.  (gelatinif erus) ,  or  g.  c.  =  gelatin-coated,  after  the  term 
for  pill.  The  terms  "  keratin-coated  "  and  "  salol-coated "  are 
best  written  in  English.  To  order  that  powders  should  be  put 
in  waxed  papers,  write  for  chart,  cerat.  (chartas  ceratas).  Such 
are  used  for  efflorescent  or  deliquescent  drugs,  and  for  the  latter 
especially  if  the  patient  is  to  be  at  the  seashore  or  aboard  ship. 

(6)  In  verbs — ft.  for  fiat  or  fiant  (let  it  or  them  be  made), 
div.  for  divide  (divide),  M.  for  misce  (mix),  S.  or  Sig.  for  Signa 
(label),  bull,  for  bulliat  or  bulliant  (let  it  or  them  boil). 

An  example  of  the  use  of  these  abbreviations  might  be:  Ft. 
pil.  argent.  No.  xij  (Fiant  pilula  argentifera,  numero  duodecim) 
=  let  twelve  silver-coated  pills  be  made. 

III.  In  the  Directions  for  the  Label. — (a)  Relating  to  quan- 
tity— gtt.  (drop),  5j  (one  teaspoonf ul) ,  3ij  (one  dessertspoonful), 
oiv    (one  tablespoonful),  cochl.  parv.,  coch.   mag.    (cochlearia 
parva,  magna  =  small  or  large  spoon).     The  term  cochlearia 
might  properly  be  abandoned. 

(6)  Relating  to  the  time  of  taking — h.  (hour),  min.  (minute); 
stat.  (statim  =  at  once);  a.  c.  (ante  cibum  =  before  eating), 
p.  c.  (post  cibum  =  after  eating);  q.  h.,  q.  2  h.,  q.  3  h.,  q.  4  h. 
(quaqua  hora  =  every  hour,  every  two  hours,  etc.);  o.  d.,  b.  i.  d., 
t.  i.  d.,  4  i.  d.  (omne  die,  bis  in  die,  ter  in  die  =  daily,  twice  a  day, 
three  times  a  day,  etc.) ;  o.  m.,  o.  n.  (omne  mane  =  each  morning, 
omne  nocte  =  each  night);  M.  et  N.  (mane  et  nocte  =  morning 
and  night;  also  written  "mane  nocteque,"  and  "a.  m.  et  p.  m."); 
s.  o.  s.,  p.  r.  n.  (si  opus  sit  =  if  there  is  necessity;  pro  re  nata  = 
when  required).  In  some  circles  a  distinction  is  made,  s.  o.  s. 
referring  to  one  dose  only,  and  p.  r.  n.  to  any  number,  its  inter- 
pretation being,  "whenever  needed." 


PRACTICE.  IN   BULK   PRESCRIPTIONS  599 

(c)  In  aq.  (in  aqua  =  in  water). 

An  example  of  the  use  of  such  directions  would  be : 

Sig. —  3j  in  aq.  t.i.  d.  10  min.  a.c.  =  a  teaspoonful  in  water 
three  times  a  day,  ten  minutes  before  meals. 

Though  it  would  certainly  be  the  safest  plan  to  write  directions 
for  the  label  in  full  English,  it  is  not  the  custom  to  do  so. 

IV.  Special  abbreviations,  usually  placed  at  the  top  of  the 
prescription  blanks,  are  P.P.  =  poor  patient,  and  ne  rep.  =  ne 
repetatur  (not  to  be  repeated). 

Observe  that  the  proper  abbreviation  for  drops  is  gtt.  and  not 
gtts.,  for  grains  is  gr.,  for  grams  is  gm.,  and  for  pill  or  pills  is 
pil.  not  pill. 

I.    PRACTICE  IN  BULK  PRESCRIPTIONS 

According  to  the  forementioned  rules,  write  out,  correctly 
using  approved  abbreviations,  the  following  prescriptions. 
Ascribe  each  prescription  to  some  person,  e.  g.,  For  John,  For 
Willie,  For  Mr.  William  Hawkes,  Jr.,  For  Mrs.  Brown,  etc., 
date  the  prescription,  and  sign  with  your  own  name. 

A.  Liquids. — i.  Three  ounces  of  rhubarb  and  soda  mixture. 
Directions :  Two  teaspoonfuls  in  a  wineglass  of  water  three  times 
a  day,  two  hours  after  eating. 

2.  Twenty-four  teaspoonful  doses,  each  dose  containing  5 
minims  of  fluidextract  of  cascara,  and  rhubarb  and  soda  mixture 
to  make  up  the  remainder.     Directions,  a  teaspoonful  in  a  wine- 
glass of  water  an  hour  before  luncheon  and  dinner  and  at  bed- 
time. 

3.  Twelve  dessertspoonful  doses,  each  containing  5  grains  of 
sodium  bicarbonate,  40  minims  of  milk  of  magnesia  (magma 
magnesiae,  N.  F.),  and  rhubarb  and  soda  mixture  to  make  the 
total.     Direct  that  the  dose  is  to  be  taken  in  a  little  water  one 
hour  after  meals. 

4.  Six  ounces  of  infusion  of  digitalis,   fresh  made  (recens, 
recentis).     Dose,  one  teaspoonful  with  water  every  four  hours. 
Have  the  name  of  the  preparation  placed  upon  the  label. 

5.  Twelve  doses  of  infusion  of  digitalis,  each  containing  fifteen 
grains  of  potassium  acetate.     Directions,  a  tablespoonful  with 
water  after  each  meal. 

6.  Sixteen  two-dram  doses  of  the  elixir  of  the  phosphates  of 
iron,  quinine  and  strychnine,  a  dose  to  be  taken  in  water  three 
times  a  day  after  meals. 

7.  Half  an  ounce  of  the  tincture  of  nux  vomica.     Directions, 
10  drops  in  water  three  times  a  day,  fifteen  minutes  before  eating. 
With  this,  order  a  Barnes  medicine-dropper. 

8.  One  ounce  of  Fowler's  solution.     Directions:    Begin  with 


6oO  PHARMACOLOGY   AND    THERAPEUTICS 

three  drops  in  water  three  times  a  day  after  eating,  and  increase 
one  drop  per  dose  each  day  till  the  dose  is  ten  drops. 

9.  One  ounce  of  a  saturated  solution  of  potassium  iodide. 
Directions :  Fifteen  drops  in  a  wineglass  of  water  after  each  meal. 
(Solutio,  solutionis  (fem.)  means  a  solution  of  any  kind.     Liquor, 
liquoris  (masc.)  is  the  official  title  of  an  aqueous  solution  of  non- 
volatile substances.) 

10.  Two  drams  each  of  tincture  of  ferric  chloride,  glycerin, 
and  water.     Place  in  wide-mouth  bottle  (pone  in  iv.  m.  hot.). 
Direct  that  it  be  employed  to  swab  the  throat  every  three  hours, 
and  order  the  druggist  to  send  a  throat  brush  and  a  Seidlitz 
powder.     (The  English  name,  not  the  U.  S.  P.  Latin  name,  is 
regularly  employed  for  the  last  mentioned.) 

11.  Three  ounces  of  a  saturated  solution  of  boric  acid.     Di- 
rections :  Use  warm  in  eye-cup  three  times  a  day.     Order  an  eye- 
cup  sent  with  it. 

12.  Half  an  ounce  each  of  oil  of  turpentine  and  camphorated 
oil.     Directions:   Rub  throat  twice  a  day  and  cover  with  flannel. 
Send  a  mustard-leaf  also. 

13.  Twenty  grains  of  salicylic  acid  and  sufficient  flexible 
collodion  to  make  a  quarter  of  an  ounce.     Directions:   Paint  on 
the  corn  every  night. 

14.  Two  doses,  each  containing  15  grains  of  chloral  hydrate 
and  30  grains  of  sodium  bromide,  dissolved  in  cinnamon  water. 
Directions :   One  tablespoonful  with  water  at  once,  and  the  other 
tablespoonful  two  hours  later  if  needed. 

15.  Twenty-four  tablespoonful  doses  of  emulsion  of  cod-liver 
oil.     Direct  that  the  dose  be  taken  three  times  a  day  after  meals. 

1 6.  Take  half  an  ounce  of  buchu,  make  into  an  infusion  with 
five  ounces  of  boiling  water,  strain,  and  add  two  drams  of  potas- 
sium bicarbonate  and  sufficient  cinnamon  water  to  make  half  a 
pint.     Directions:    A   tablespoonful  every  four  hours.     (How 
much  potassium  bicarbonate  is  there  in  each  dose?) 

17.  Take  half  a  dram  of  alum  and  two  drams  of  lead  acetate, 
dissolve  separately  in  distilled  water,  mix  the  solutions,  add  dis- 
tilled water  to  make  the  total  six  ounces,  and  filter.     Directions: 
Keep  dressing  wet.     (Unless  directed  to  filter  out  the  lead  sul- 
phate formed,  the  pharmacist  would  leave  it  in  and  apply  a 
"shake-before-using"  label.) 

1 8.  Take  four  ounces  of  linseed  oil,  two  ounces  of  syrup  of 
wild  cherry,  the  requisite  amount  of  acacia  (the  requisite  amount 
=  q.s.),  and  water  enough  to  make  an   eight-ounce  emulsion. 
Directions:   Two  teaspoonfuls  every  four  hours. 

19.  One  ounce    each    of    compound    tincture    of    lavender, 
aromatic  spirit  of  ammonia,  and  spirit  of  chloroform.     Direc- 


PRACTICE   IN   PRESCRIPTIONS  FOR  OBJECTS    TO   BE    COUNTED      6oi 

tions :  A  teaspoonf ul  in  a  wineglass  of  hot  water  when  needed  for 
flatulence. 

20.  Two  ounces  of  a  solution  of  nitrate  of  silver,  10  grains  to 
the  ounce.  Put  in  a  dark  bottle,  and  label  what  it  is  (in  a  dark 
bottle  =  in  vitro  nigro  or  in  vitro  obscuro). 

The  following  is  a  facetious  prescription,  which  might  be  an 
effective  placebo : 

]$    Aquae  fontinalis gtt.  xv 

H.O, 

Hydrogenii  monoxidi aa  5  ss 

Illius  repetitae 5  j 

Ejusdem 3  ij 

Nil  aliud q.  s.  ad  3  j 

M.  et  Sig. — Ten  drops  in  a  wineglass  of  water  every  three  hours — For 

nervousness ! 

B.  Ointments. — Write  for: 

1.  Two  ounces  of  cold  cream.     Directions:    Rub  into  skin 
night  and  morning. 

2.  Fifteen  grains  of  salicylic  acid,  one  dram  each  of  zinc  oxide 
and  precipitated  sulphur,  and  sufficient  vaseline  (petrolatum) 
to  make  one  ounce.     Directions:   Apply  to  skin  each  night. 

3.  One  and  a  half  drams  of  oil  of  cade   and  zinc  ointment 
enough  to  make  two  ounces.     Directions:    Apply  daily  to  the 
eczematous  area  without  rubbing. 

4.  Two  drams  each  of  soft  soap  and  balsam  of  Peru  with 
\Y2  ounces  of  sulphur  ointment.     Directions:    Rub  well  into 
itching  area  twice  a  day. 

C.  Powders. — Take  2  drams  of  magnesium  oxide,  4  drams  of 
sodium  bicarbonate,  and  i  dram  of  ginger;    mix  together  and 
place  in  a  box.     Directions:    A  level  teaspoonf  ul  with  half  a 
glass  of  water  at  eleven,  at  five,  and  at  bed-time. 

II.  PRACTICE  IN  PRESCRIPTIONS  FOR  OBJECTS  TO  BE 
COUNTED 

Write  for — i.  Thirty  five-grain  capsules  of  quinine  sulphate. 
Directions:  Three  at  time  of  chill,  then  one  three  times  a  day 
after  eating. 

2.  Twenty-four   capsules,    each   containing    i]/2    minims   of 
castor  oil  and  2l/2  grains  of  salol.     One  every  four  hours. 

3.  Twelve  five-grain   tablets  of  phenacetin.     One  daily  at 
4  P.  M. 

4.  Eight  one-quarter-grain  tablet  triturates  of  codeine  phos- 
phate.    One  for  cough  when  needed.     Have  name  of  drug  on 
label. 

5.  One  tube  of  hypodermic  tablets  of  morphine  sulphate,, 
each,  y&  grain.     Put  name  on  label. 


602  PHARMACOLOGY   AND   THERAPEUTICS 

6.  Two  five-grain  blue  pills.     Take  both  at  bed-time.     Send 
also  a  bottle  of  citrate  of  magnesia. 

7.  Thirty  Blaud's  pills,  silver  coated.     One  after  each  meal. 

8.  Three   compound   cathartic   pills.     Take   all   tonight   at 
bed-time. 

9.  Twelve  glycerin  suppositories.     Insert  one  each  morning 
before  breakfast. 

10.  Six  suppositories,  each  containing  %  grain  of  extract  of 
belladonna  and  made  with  cocoa-butter.     Insert  one  three  times 
a  day. 

11.  Three  suppositories  of  cocoa-butter,  each  containing  3 
grains  of  orthoform  and  half  a  grain  of  powdered  opium.     Make 
of  i5-grain  size.     Insert  one  an  hour  before  each  irrigation. 

12.  Twenty-four  cachets,  each  containing  10  grains  of  sodium 
salicylate  and  2  grains  of  acetanilid.     One  with  water  every  three 
hours. 

13.  A  lo-grain  Dover's  powder.     Take  with  a  glass  of  hot 
lemonade  after  retiring. 

14.  Six  2o-grain  powders  of  bismuth  subnitrate.     One  with 
water  four  times  a  day. 

15.  Precipitated  chalk  and  sodium  bicarbonate,  10  grains  of 
each  in  a  powder.    Order  twenty  such.     One  stirred  in  half  a 
glass  of  hot  water  three  times  a  day  two  hours  after  eating. 

16.  Fifteen  2o-grain  powders  of  sodium  bromide  in  waxed 
paper.     One  in  a  wineglass  of  water  morning  and  night. 

17.  Six  capsules,  each  containing  2^2  grains  of  purified  aloes, 
2  grains  of  extract  of  jalap,  5  grains  of  blue  mass,  %  grain  of 
extract  of  belladonna,  and  ^  minim  of  oil  of  peppermint.     One 
at  bed-time  once  a  week.     (Last  two  corrective.) 

1 8.  Twelve  pills,  each  containing  aloin,  \  grain,  extract  of 
belladonna,  y&  grain,  strychnine  sulphate,  -^  grain,  and  ipecac, 
2-V  grain.     One  each  night.     (These  pills  are  known  to  be  ready- 
made.) 

19.  Thirty  tablets,  each  containing  rhubarb,  2  grains,  sodium 
bicarbonate,  5  grains,  ipecac,  y&  grain,  tincture  of  nux  vomica, 
5  minims,  fluidextract  of  cascara,  5  minims,  and  oil  of  peppermint, 
^,7  minim  (or  q.s.).     Directions:  Two  with  a  wineglass  of  water 
three  times  a  day  two  hours  after  eating.     (These  tablets  are  of 
a  standard  formula.) 

20.  Thirty   capsules,   each   containing   ^(T   grain  of   arsenic 
trioxide,  >4  grain  of  extract  of  nux  vomica,  and  Blaud's  pill, 
5  grains — one  after  eating. 

Miscellaneous. — Take  belladonna  plaster  and  spread  it  upon 
surgeon's   adhesive   plaster    over  a   circular  area    2   inches   in 


INCOMPATIBILITY  603 

diameter.     (In  this  case  it  would  be  better  to  write  the  directions 
to  the  pharmacist  in  English.) 

Criticize  the  following  as  to — (i)  Completeness;  (2)  order 
and  correctness  of  names  of  ingredients;  (3)  correctness  of 
amounts;  (4)  safety  of  dosage;  (5)  directions. 

1.  1$       Spirit!  ammon.  aromat 5i 

2.  Rx     Mixt.  creta 3ii 

Tr.  opii Sii 

Subnitrate  bismuthum 5ii 

As  directed. 

INCOMPATIBILITY 

Incompatibility  between  two  substances  may  be  said  to  exist 
when  their  admixture  brings  about  physical  or  chemical  change 
other  than  simple  solution.  Such  a  change — (i)  may  be  desired 
in  a  prescription,  (2)  may  make  little,  if  any,  difference,  or  (3) 
may  be  undesirable.  A  chemic  reaction  may  result  in  a  pre- 
cipitate, may  show  merely  in  an  alteration  of  color,  or  may  make 
no  visible  change  at  all.  But  the  physician  should  know  in 
what  form  his  remedies  are  when  the  patient  takes  them. 

"Incompatibility"  is  a  bugaboo  raised  for  the  alarm  of  the 
prospective  prescription  writer,  and  it  is  an  unnecessary  alarm. 
For,  though  a  great  many  incompatibles  for  almost  any  active 
chemical  may  be  found  in  the  laboratory,  yet  but  few  of  these 
are  ever  likely  to  be  encountered  in  a  prescription;  and  of  those 
few,  the  result  not  infrequently  makes  no  practical  change  in  the 
medicinal  value,  or  is  deliberately  desired. 

The  following  are  those  most  likely  to  be  encountered  in  the 
practical  use  of  drugs : 

I.  Incompatibility  Depending  on  Change   of   Solvent. — (a) 
Precipitate   When   Added   to   Aqueous   Liquids. — Substances   in 
alcoholic  solution  and  insoluble  in  water;    as  in  spirits,  fluid- 
extracts,  and  tinctures,  especially  resinous  ones,  like  tincture  of 
cannabis,  benzoin,  myrrh. 

(b)  Precipitate  When  Added  to  Alcoholic  Liquids. — Substances 
in  aqueous  solution  and  insoluble  in  alcohol;  as  solutions  of  many 
salts  (sodium  sulphate,  ammonium  chloride) ,  ichthyol,  and  mucil- 
age of  acacia.  Mere  insolubility,  as  of  oils  or  bismuth  subnitrate 
in  water,  makes  these  really  incompatible  with  the  solvent;  but 
such  are  considered  under  the  head  of  "solubility." 

II.  Chemic   Incompatibility. — Rule   i:   Acids    and   salts   of 
acid  reaction  are  incompatible  with  alkalies  and  salts  of  alkaline 
reaction  and  the  halogen  salts,  as  hydrochloric  acid  or  potassium 
bitartrate  with  sodium  bicarbonate  or  magnesia. 

Rule  2 :  Highly  oxidized  substances,  like  chromium  trioxide 
(chromic  acid),  potassium  permanganate,  and  potassium  chlorate 


604  PHARMACOLOGY   AND   THERAPEUTICS 

are  decomposed  by  organic  matter.  Potassium  permanganate 
in  solution  turns  brown;  dry  potassium  permanganate  or  chromic 
acid  may  take  fire  or  explode.  Potassium  chlorate,  when  rubbed 
with  sulphur,  hypophosphites,  ammonium  chloride,  tannic  acid 
or  other  organic  substance,  will  explode  violently. 

Rule  3:  Silver  nitrate  is  incompatible  with  organic  material 
and  turns  to  black  oxide  or  black  metallic  silver.  With  chlorides 
or  hydrochloric  acid  it  forms  the  insoluble  silver  chloride. 

Rule  4:  Mild  mer curous  chloride  (calomel)  is  incompatible 
with  sodium  carbonate  and  lime-water.  With  the  latter  it  makes 
a  black  precipitate  of  mercurous  hydroxide,  and  forms  "black 
wash,"  sometimes  employed  as  an  application  to  venereal  sores. 

Calomel  is  insoluble  in  water  or  alcohol,  comparatively  inert 
chemically,  and  bland  to  tissues. 

Rule  5:  Corrosive  mercuric  chloride  (corrosive  sublimate)  is 
incompatible  with  iodides,  many  metallic  salts,  alkaloidal  salts, 
tannic  acid,  lime-water,  and  albumin. 

With  excess  of  lime-water  it  makes  a  yellow  precipitate  of 
mercuric  oxide,  and  forms  "yellow  wash,"  employed  as  an 
application  to  venereal  sores.  When  the  mercury  salt  is  in  excess, 
the  precipitate  is  red  oxychloride. 

With  soap,  as  on  the  surgeon's  hands,  its  antiseptic  power  is 
destroyed. 

With  potassium  iodide  it  forms  mercuric  biniodide — 2  KI  -+- 
HgCl2  =  2  HC1  +  Hglo.  The  iodide  is  of  a  brilliant  scarlet 
and  dissolves  in  excess  of  the  potassium  iodide.  These  two  salts 
are  often  prescribed  together  to  form  the  biniodide. 

In  albumin,  as  in  white  of  egg  or  milk,  we  have  the  antidote 
when  the  drug  is  swallowed. 

Rule  6:  Lead  acetate  decomposes  alum  and  other  sulphates 
and  the  iodides,  and  tends  to  precipitate  many  organic  substances, 
e.  g.,  glucosides,  from  their  solution. 

The  admixture  with  alum  makes  Burow's  solution.  The 
precipitate  of  lead  sulphate  should  be  filtered  off.  The  pre- 
cipitate with  the  iodide  is  lead  iodide  of  a  brilliant  yellow. 

Rule  7:  Ferric  salts — (a)  make  "ink"  with  tannic  acid;  (b) 
make  blue  to  reddish  or  purple  colors  with  compounds  of  the 
phenol  group,  such  as  phenol,  resorcin,  salicylates,  etc.;  (c) 
make  a  red  color  with  acetates,  and  (d]  form  a  dirty-brown  pre- 
cipitate with  alkalies  or  alkaline  salts. 

Rule  8:  Tannic  acid  is  incompatible  with  alkaloidal  saltsr 
dry  potassium  chlorate  (explodes),  metallic  salts,  gelatin,  and 
albumin.  With  ferric  salts  it  makes  "ink."  For  salts  of  alka- 
loids and  antimony  it  is  the  local  antidote. 

It  occurs  in  many  vegetable  drugs,  and  preparations  of  these 


INCOMPATIBILITY  605 

may  not  only  precipitate  alkaloidal  salts,  but  may  change  the 
gelatin  coating  of  a  pill  or  a  gelatin  capsule  to  a  tough,  leathery, 
insoluble  substance.  Alcohol,  as  in  tinctures,  may  prevent  the 
precipitation  of  alkaloidal  salts  by  tannic  acid. 

Rule  9:  Chloral  hydrate  decomposes  to  chloroform  under  the 
influence  of  strong  alkalies;  and  when  mixed  with  camphor, 
menthol,  thymol,  and  similar  substances,  undergoes  a  physical 
change  to  a  liquid. 

Rule  10:  Alkaloidal  salts  are  incompatible  with — 

(a)  Alkalies — the  precipitate  is  the  pure  alkaloid. 

(b)  Tannic  acid — the  precipitate  is  the  insoluble  tannate. 

(c)  Iodine,   iodides   and   bromides — the   precipitate   is   the 
iodide  or  bromide. 

(d)  Mercuric    bichloride — the    precipitate    is    an    insoluble 
double  salt. 

Quinine  in  addition  is  especially  precipitated  by  salicylates 
and  benzoates. 

All  these  precipitates  are  more  soluble  in  alcohol  than  water, 
so  may  not  show  in  tinctures  and  other  alcoholic  liquids. 

Rule  1 1 :  Glucosides  are  incompatible  for  the  most  part  with 
lead  acetate  and  tannic  acid,  and  are  decomposed  by  the  mineral 
acids. 


INDEX 


ABBREVIATIONS  in  prescription  writing, 

597 

special,  in  prescription  writing,  599 
A.  B.  C.  mixture,  102 
Abortifacients,  567 
Abrin,  27 

Abrus  precatorius,  27 
Absinthe,  320 
cordial,  320 
Absolute  alcohol,  316 
Absorption,  to  promote,  counterirritants 

for,  78 

Acacia,  28,  29 
Accelerator  system,  150 
depression,  151 
stimulation,  150,  151 
Acetanilid,  462 
excretion,  468 
untoward  effects,  468 
Acetanilid-salicylic  acid,  462 
Acetanilidum,  462 
Acetates,  89 
Acetic  acid,  89 
diluted,  89 
glacial,  89 

Aceto-arsenite  of  copper,  546 
Acetonuria  in  anesthesia,  304 
Acet-phenetidin,  excretion,  468 

untoward  effects,  468 
Acet-phenetidinum,  462 
Acetum,  160 

definition,  40 
Acetyl-salicylic  acid,  484 
poisoning  from,  485 
Acid,  acetanilid-salicylic,  462 
acetic,  89 

diluted,  89 
acetyl-salicylic,  484 
aconitic,  231 
agaric,  412 
arsenic,  541 
arsenous,  541 

solution  of,  541 
benzoic,  501 
boric,  as  preservative,  500 

poisoning  from,  501 
caffeotannic,  264 
camphoric,  412 
dose,  412 


Acid,  carbolic,  504.     See  also  Phenol. 

burns  from,  alcohol  as  preventive, 

354       t 
cinnamic,  501 
citric,  88,  90 

effect  of,  on  clotting  of  blood,  89 

in  typhoid  fever,  89 
crotonic,  136 
di-ethyl  barbituric,  365 
ergotinic,  567 

filicic,  amorphus,  for  tape-worms,  119 
formic,  89 

in  rheumatism,  89 
glacial  acetic,  89 
gymnemic,  109 
hydriodic,  diluted,  555 
hydrochloric,  therapeutics,  87 
hydrocyanic,  426 

diluted,  426 

preparations,  426 

therapeutics,  427 
lactic,  89 

for  tuberculous  ulcers  of  throat,  89 

in  diabetes,  90 
malic,  90 
nitric,  86 

dilute,  therapeutics,  88 

for  warts  or  nevi,  87 

therapeutics,  87 
nitrohydrochloric,  86 

dilute,  therapeutics,  88 

diluted,  86 
oxalic,  90 

poisoning  from,  90 
para  -  sulphondi  -  chloramino- benzoic, 

495 
phenyl-cinchoninic,  487 

in  gout,  487,  488 
phenyl-quinoline-carboxylic,  487 
phosphoric,  dilute,  therapeutics,  88 
phosphorous,  553 
salicylic,  480 

absorption,  481 

administration,  484 

as  surgical  antiseptic,  483 

dose,  480 

excretion,  482 

hypodermatic  use,  484 

in  bromidrosis,  483 

607 


6o8 


INDEX 


Acid,  salicylic,  in  chorea,  483 

in  corns,  483 

in  diabetes,  484 

in  gout,  484 

in  pain,  484 

in  rheumatism,  483 

in  skin  diseases,  483 

in  sweating  of  feet  and  hands,  483 

in  warts,  483 

intravenous  administration,  484 

pharmacologic  action,  480-482 

poisoning  from,  482 

preparations  and  doses,  480 

rectal  administration,  484 

therapeutics,  483 

toxicology,  482 
succinyl  disalicylic,  485 
sulphuric,  action  of,  78 

aromatic,  86 

in  night-sweats  of  tuberculosis,  88 
sulphurous,  493 
tannic,  29,  114 

and  alkaloids,  incompatibility,  22 

of  coffee,  264 

of  tea,  265 

therapeutics,  115 
tartaric,  88,  90 
trichloracetic,  89 
trichlorethyl-glycuronic,  361 
uric,  252 
valerianic,  394 
waters,  147 
Acidol,  88 
Acidosis  in  anesthesia,  304 

sodium  bicarbonate  in,  95 
Acids,  caustic,  78 
fruit,  90 
inorganic,  86 

action,  86 

poisoning  from,  treatment,  87 

therapeutics,  87 

toxicology,  86 
organic,  88 

plant,  and  their  salts,  20 
Acidum  aceticum,  89 
citricum,  88 
formicum,  89 
lacticum,  89 
nitrohydrochloricum,  86 
salicylicum,  480 
sulphuricum  aromaticum,  86 
tannicum,  114 
tartaricum,  88 
Acne,  calcium  sulphide  in,  124 

potassa  sulphurata  in,  1 24 
Aconine,  231 
Aconite,  231 

absorption  of,  232 
administration,  236 
constituents,  231 
excretion,  235 
fluidcxtract,  dose,  231 


Aconite  in  fevers,  236 

in  pain,  235 

in  reducing  high  arterial  pressure  in 
chronic  interstitial  nephritis,  233 

in  trifacial  neuralgia,  236 

pharmacologic  action,  232-235 

poisoning  from,  235 
treatment,  235 

preparations  and  doses,  23 1 

Squibb's  test  for,  232 

therapeutics,  235 

tincture,  dose,  231 

toxicology,  235 
Aconitic  acid,  231 
Aconitine,  231 

dose,  232 
Aconitum,  231 

napellus,  231 

Acrinyl  isothiocyanate,  26 
Acroparesthesia,  paroxysms  of,  quinine 

in,  477 
Actinomycosis,  copper  sulphate  in,  529 

iodides  in,  558 
Active  constituents  of  drugs,  19,  20 

principles,  44 
Adalin,  366 

Addison's  disease,  epinephrine  in,  205 
Adenin,  252 
Adeps,  30 

lanae  hydrosus,  32 
Adjectives,  Latin,  589 
Administration,  52,  62 

by  hypodermatoclysis,  55 

by  inunction,  55 

by  mouth,  53 

by  rectum,  55 

by  skin,  55 

by  veins,  55 

channel  of,  dose  and,  51 

frequency  of,  dose  and,  52 

hypodermatic,  53 
advantages,  54 
disadvantages,  54 

intracutaneous,  54 

intramuscular,  53,  54 

intravenous,  55 

methods,  53 

subcutaneously,  53 
superficial,  54 

through  lungs  by  inhalation,  55 

time  of,  56 

dose  and,  52 
Adonidin,  161 
Adonis  vernalis,  160 
Adrenaline,  196.     See  also  Epinephrine. 
Adrenals,  relation  of  thyroid  gland  to,  561 
Adverbs,  Latin,  590 
/Ether,  284 
/Ethylis  carbamas,  366 

chloridum,  312 
Agar  to  give  bulk  and  soft  consistency 

to  feces,  125 


INDEX 


609 


Agar-agar  to  give  bulk  and  soft  consist- 
ency to  feces,  125 
Agaric  acid,  412 

deadly,  443 

fly,  442,  443 
Agaricin,  41 2 

dose,  412 

in  excessive  sweating,  412 
Agaricus  campestris,  443 
Age,  dose  and,  48 
Ague,  brass  founder's,  530 
Air,  superheated,  450 
Albargin,  534 
Albolene,  liquid,  33,  125 

solid,  33    ' 

Albuminuria,  functional,  iron  in,  540 
Alcohol,  316 

absolute,  316 

absorption,  323 

as  anhidrotic,  354 

as  antiseptic,  353 

as  cooling  lotion,  353 

as  hypnotic,  354 

as  narcotic  or  sedative,  354 

as  preservative,  515 

as  preventive  of  carbolic  acid  burns, 
354 

contraindications,  355 

dehydrated,  316 

denatured,  316 

deodorized,  316 

diluted,  316 

elimination,  341 

ethyl,  316 

fecundity  and,  352 

food  value,  331-336 

grain-,  316 

heredity  and,  352 

in  convalescence,  354 

in  diabetes,  343 

in  fever,  354 

in  gout,  343 

in  insomnia,  354 

in  shock,  354 

in  trigeminal  neuralgia,  354 

medicinal  quantities,  effects  of.  352 

methyl,  355 

blindness  from,  355,  356 
poisoning  from,  355 

narcosis,  stages,  331 

pathologic  effects  on  organs,  350 

pharmacologic  action,  321-343 

poisoning  from,  344 
after-effects,  345 
treatment,  345 

preparations,  316 

resistance  to  disease  and,  352 

salicyl,  25 

stupor  from,  344 

therapeutics,  353 

to  furnish  food  and  stimulation,  354 

to  harden  skin,  354 

39 


Alcohol  to  prevent  or  check  a  cold,  354 

tolerance,  343 

toxicology,  344 

wood, 355 

Alcoholic  liquids,  40 
Alcoholism,  acute,  344 
treatment,  345 

chronic,  Korsakoff's  psychosis  in,  347 
treatment,  347 

cure  of,  349 

Lambert's  treatment,  349 
Ales,  317 

Alimentary  tract,  effect  of  sodium  bi- 
carbonate on,  94 
Alkalies  and  alkaloids,  incompatibility, 

22 

caustic,  78,  91 

mild,  91 
Alkaline  saline  waters,  147 

waters,  147 
Alkaloidal  salts,  21 

differences  in  physiologic  actions,  24 
solubility  of,  21 
Alkaloids,  20 

and  alkalies,  incompatibility,  22 

and  bromides,  incompatibility,  22 

and  iodides,  incompatibility,  22 

and  iodine,  incompatibility,  22 

and  mercuric  chloride,  incompatibility, 
22 

and  tannic  acid,  incompatibility,  22 

artificial,  23 

incompatibles,  22 

nomenclature,  21 

occurrence,  22 

opium,  373 

isoquinoline,  373 
phenanthrene,  373 

physical  character,  22 

pure,  21 

solubility  of,  21 

solubility  of,  21 

taste  of,  22 
Allyl  isothiocyanate,  26 

sulphocarbamide,  80 
Almond,  bitter,  oil  of,  25,  426 
spirit  of,  426 

oil,  30 

water,  bitter,  426 
Aloes,  133 

dose,  133 

pills  of,  133 

preparations,  133 

tincture  of,  133 
Aloin,  26,  133 
Aloinum,  133 
Alum,  535 

burnt,  536 

waters,  147 
Alumen,  535 

exsiccatum,  536 
Aluminis,  535 


6io 


INDEX 


Aluminium,  535 
acetate,  solution  of,  536 
as  antiseptic  and  disinfectant,  500 
chloride  in  sweating  of  hands,  feet,  and 

axillae,  536 
Aluminum,  535 
Alypine,  423 

Amanita  muscaria,  442,  443 
phalloides,  27,  442,  443 
toxin,  27 
verna,  443 
Amaroids,  26 
Amaurosis,  quinine,  474 
Amblyopia,  quinine,  474 

tobacco,  435 

Amebic  colitis,  quinine  in,  476 
dysentery,  calcium  permanganate  in, 

S4i 

emetine  in,  566 
ipecac  in,  566 
quinine  in,  478 
American  hellebore,  236 
Aminopurins,  252 
Ammonia,  absorption  of,  219 

effects  after,  222 
administration,  222 
aromatic  spirit,  218 
as  antacid  carminative,  223 
as  counterirritant,  222 
as  expectorant,  223 
as  reflex  circulatory  stimulant,  222 

respiratory  stimulant,  222 
chloride  of,  223 
contraindication,  223 
elimination  of,  222 
liniment,  218 
liver  in  disposal  of,  220 
muriate  of,  223 

pharmacologic  action,  218-222 
poisoning  from,  222 
treatment,  222 
preparations,  218 
therapeutics,  222 
toxicology,  222 
water,  218 

stronger,  218 
Ammoniated  mercury,  ointment  of,  as 

antiseptic,  519 
tincture  of  valerian,  107 
Ammonium,  218 
acetate,  224 

solution  of,  224 
alum,  535 
benzoate,  225 
bromide,  225 
carbonate,  218 
chloride,  223 

absorption  of,  223 
action  of,  223 
excretion  of,  224 
in  acute  pharyngitis,  224 
in  bronchitis,  224 


Ammonium  chloride  in  laryngitis,  224 
pharmacologic  action,  223,  224 
therapeutics,  224 
preparations,  218 
salicylate,  225 
valerate,  225 
Amorphous  filicic  acid  for  tape-worms, 

119 

Amygdala  amara,  426 
Amygdalin,  25 
Amyl  nitrite,  239 
dose,  239 
effect,  242 

in  angina  pectoris,  245 
in  chloroform  collapse,  245 
Amylene  hydrate,  366 
Amylis  nitris,  239 
Amylum,  28 

Analgesia,  spinal,  with  cocaine,  414,  421 
Analgesic  antipyretics,  462 
administration,  470 
in  pain,  470 

pharmacologic  action,  463-468 
therapeutics,  469 
to  overcome  fever,  470 
toxicology,  468,  469 
Anaphylactic     shock,     epinephrine     to 

check,  205 

Anaphylaxis,  atropine  in,  408 
Anatomic  material,  preservatives  for,  515 
Anemia,  cholesterol  in,  32 
iron  in,  540 
lecithin  in,  555 
pernicious,  cholesterol  in,  32 
sodium  cacodylate  in,  542 
transfusion  of  blood  in,  226 
Anesthesia,  acetonuria  in,  304 
acidosis  in,  304 

atropine  as  preliminary  to,  408 
Bier's  vein,  422 

by  intratracheal  insufflation,  307 
by  pharyngeal  insufflation.  309 
chloroform,  292,  300 
advantages,  300 
collapse  in,  amyl  nitrite  in,  245 
camphor  in,  309 
treatment,  309 
contraindications,  304 
dangers,  301-304 
delayed  poisoning  from,  302 
intravenous,  307 
phagocytic   activity  of  leukocytes 

after,  305 

preventive  measures  in,  304 
cocaine  hydrochloride,  420 
collapse  in,  oxygen  in,  580 

treatment,  309 
colonic,  306 

cyanosis  in,  treatment,  309 
effect,  on  immunity,  305 

on  infections,  305 
Epsom  salt,  313 


INDEX 


Anesthesia,  ether,  292 

administration,  general  remarks,  305 

of  sodium  bicarbonate,  299 
after-effects,  297 

chloretone  as  preliminary  to,  364 
collapse  in,  296 
saline  infusion  in,  309 
treatment,  309 
conjunctivitis  after,  298 
danger-signs,  296 
distention  of  stomach  and  intestines 

for,  297 
first  stage,  294 
fourth  stage,  296 
having  stomach  empty,  299 
helpful  measures  in,  298 
indications,  299 

injection  of  atropine  sulphate  in,  299 
intravenous,  307 
kidneys  after,  298 
nausea  after,  297 
pain  in  back  after,  297 
phagocytic   activity   of   leukocytes 

after,  305 
postoperative  gastric  or  intestinal 

paralysis  after,  298 
preliminary  administration  of  seda- 
tive drugs,  298 
anesthetization  with  chloroform, 

298 
with    nitrous    oxide    or    ethyl 

chloride,  298 
feeding  with  carbohydrates  and 

water,  299 

preventive  measures  in,  298 
reassuring  patient,  299 
recovery  from,  297 
respiratory  troubles  after,  298 
second  stage,  295 
sore  tongue  after,  298 
third  stage,  295 
thirst  after,  297 
untoward  sequels,  298 
vomiting  after,  297 
warming  vapor,  299 
ethyl  bromide,  313 

chloride,  312 
false,  297 
Gwathmey's  oil-ether  colonic  method, 

306 

intravenous,  307 
Bier's,  425 
local,  425 

paraldehyd  for,  307 
with  chloroform,  307 
with  cocaine,  422 
with  ether,  307 
laughing-gas,  310 
local,  epinephrine  to  prolong,  205 
magnesium  sulphate,  313 
morphine  as  preliminary  to,  387 
nitrogen  monoxide,  310 


Anesthesia,  nitrous  oxide,  310 

objects,  292 

pulse  in,  309 

rectal,  306 

Schleich's  infiltration,  425 

scopolamine-morphine,  409 

scopolamine-narcophin,  409 

spinal,  in  strychnine  poisoning,  279 
with  cocaine,  414,  415,  421 
with  stovaine  and  strychnine,  41  e 

therapeutics,  310 

untoward  symptoms,  treatment,  309 
Anesthesin,  424 
A/iesthetics,  general,  284 
Aneurysm,  gelatin  in,  71 

of  aorta,  digitalis  in,  195 
Angina  pectoris,  amyl  nitrite  in,  245 

Hoffmann's  anodyne  in,  288 
Angioneurotic  edema,  calcium  in,  100 
Anhidrotics,  411 
Animal  charcoal,  109 
purified,  109 

experimentation,  58 

Ankylostoma  americana,  treatment,  117 
Anoci-association,  Crile's,  249,  250 
Anodyne,  Hoffmann's,  dose,  284 
in  angina  pectoris,  288 
in  dyspnea,  288 
in  hysteria,  288 
in  spasm,  288 
therapeutics,  288 
Antacids,  91 

as  antemetics,  112 

not  of  alkaline  reaction,  101 

of  alkaline  reaction,  91 
Antagonists,  57 
Antemetics,  112 
Anthelmintics,  115 
Anthracene  derivatives,  131 
action  on  bowel,  132 
therapeutics,  132 
Anti-bitters,  109 
Anti-diarrheics,  146 
Antiformin,  494 
Antihysterics,  393 
Anti-malarial  antipyretics,  470 
Antimony,  552 

and  potassium  tartrate,  552 

in  kala-azar,  552 

in  Leishmaniosis,  552 

in  malaria,  552 

in  oriental  sore,  552 

in  trypanosomiasis,  552 

pharmacologic  action,  552 

poisoning,  552 

preparations  and  doses,  552 

wine  of,  552 
Antiphlogistine,  76 
Antipyretic  drugs,  461 
Antipyretics,  461 

analgesic,  462 

administration,  470 


6l2 


INDEX 


Antipyretics,  analgesic,  in  pain,  470 
pharmacologic  action,  463-468 
therapeutics,  469 
to  overcome  fever,  470 
toxicology,  468,  469 

anti-malarial,  470 

antirheumatic,  480 
Antipyrina,  462 
Antipyrine,  24,  462 

excretion,  468 

in  chorea,  469 

in  diabetes,  469 

in  nasal  hemorrhage,  469 

in  tuberculous  laryngitis,  469 

in  whooping-cough,  469 

pharmacologic  action,  463-468 

poisoning  from,  468,  469 

salicylate,  462 

therapeutics,  469 

untoward  effects,  468 
Antirheumatic  antipyretics,  480 
Antiseptic  iodine  compounds,  499 

solution,  504 
Antiseptics,  488 

classification,  491 

psychic,  504 

tests  for  value,  489 
Antispasmodics,  393 
Antisyphilitics,    mercury    preparations, 

Antithyroid  preparations,  562 

Antithyroidin,  562 

Antitoxins,  preservatives  for,  515 

Anuria,  glucose  in,  70 

Anus,  diseases  of,  cocaine  in,  421 

itching  of,  epinephrine,  in,  205 
Aorta,  aneurysm  of,  digitalis  in,  195 
Aortic  insufficiency,  digitalis  in,  193 

stenosis,  digitalis  in,  194 
Aortitis,  digitalis  in,  195 
Aperient,  122 
Apocodeine,  388 

as  cathartic,  124 
Apocynein,  160 
Apocynin,  160 
Apocynum,  160 
Apolysin,  463 
Apomorphine,  23 

hydrochloride,  in 
Apothecaries'  system,  prescriptions  of, 

weights  and  measures,  43 
exact  equivalents,  44 
Appalache  tea,  253 
Appetite  gastric  juice,  107 

juice,  324 
Apple,  bitter,  dose,  13? 

cider,  318 
Apple-brandy,  319 
Aqua,  39 

ammonia;,  218 
fortior,  218 


Aqua  amygdalae  amarse,  426 
Aqueous  liquids,  39 
Arabinose,  28 
Areas,  Head's,  74 
Argentum,  533 
Argyria,  535 

conjunctival,  535 
Argyrol,  534 

Arhythmia  from  digitalis,  166 
phasic,  from  digitalis,  166,  176 
sinus,  digitalis  in,  189 

from  digitalis,  166 
Aristol,  490,  504 
Aromatic  bitters,  108,  109 
elixir,  106,  320 
spirit  of  ammonia,  218 
sulphuric  acid,  86 
Aromatics,  102 

for  prescription,  585 
pharmacologic  action,  102-104 
Arrowroot  starch,  28 
Arsacetin,  542 
Arsenic,  541 
absorption,  543 
acid,  541 

administration,  549 
excretion,  545 
melanosis,  548 
organic  compounds,  541 
pharmacologic  action,  543-546 
poisoning,  acute,  546 

iron  as  antidote,  537,  547 
treatment,  547 
chronic,  547 

treatment,  548 
cumulative,  547 
preparations  and  doses,  541 
therapeutics,  548 
tolerance,  545 
toxicology,  546 
trioxide,  541 
white,  541 

Arsenical  waters,  147 
Arsenic-eaters,  545 
Arseniureted  hydrogen,  546 
Arsenophenylglycin,  542 
Arsenous  acid,  541 

solution  of,  541 
iodide,  541 
Arsenum,  541 
Arterial  dilators,  239 
pressure,  154 

high,  digitalis  in,  IQI 
in  chronic   interstitial   nephritis, 

aconite  for  reducing,  233 
increased,  from  digitalis,  1 70 
raising,  mechanical  measures  for, 

225 

regulators  of,  155 
Arteries,  blood  in,  decrease  of,  causes,  149 

increase  of,  causes,  149 
changes  in  caliber,  152 


INDEX 


6i3 


Arteries,  conditions  of,  influence,  on  use- 
fulness of  digitalis,  192 

connective-tissue    changes    in,    from 
epinephrine,  201 

contraction  of,  153 

coronary,  constriction  of,  from  digi- 
talis, 176 

cutaneous,  action  of  digitalis  on  cir- 
culation through, 180 

dilatation  of,  153 

measures    for   increasing   volume    of 
blood,  in,  225 

peripheral,  contraction  of,  from  digi- 
talis, 178 

pulmonary,  action  of  digitalis  on  cir- 
culation through,  180 

systemic,  action  of  digitalis  on  circula- 
tion through,  178 

Arterioles  as  regulators  of  arterial  pres- 
sure, 155 

cutaneous,  caliber,  154 
Arteriosclerosis,  digitalis  in,   195 

from  smoking,  435 
Arthritis,  dry,  vaseline  in,  33 

magnesium  sulphate  in,  315 

rheumatoid,  liquid  petrolatum  in,  33 

thyroid  gland  in,  562 
Artificial  alkaloids,  23 

emulsion,  40 

leech,  248 

respiration   in   strychnine   poisoning, 

2/9 

Asagraea  officinalis,  237 

Ascaris  lumbricoides,  remedies  for,  116 

Aspergillus  oryzae,  85 

Aspidium,  oleoresin  of,  for  tape-worms, 

iiQ  , 

poisoning  from,  119 
Aspidosperma  as  expectorant,  563 
Aspidospermine  as  expectorant,  563 
Aspirin,  484 

poisoning  from,  485 
Assay  processes,  44 
Assayed  drugs,  44 
Asthma,  anterior  lobe  extract  of  pituitary 

gland  in,  211 

bronchial,  calcium  in,  100 
epinephrine  in,  202 
oxygen  in,  580 
potassium  nitrate  in,  240 
powders,  245 
spasmodic,  lobelia  in,  428 
sparteine  suphate  in,  428 
stramonium  in,  408 
tobacco  in,  430 
Astringents,  113 
metallic,  113 
vegetable,  114 

Ataxia,  locomotor,  salvarsan  in,  550 
Atophan,  487 
Atoxyl,  542 
Atropa  belladonna,  394 


Atrophy,  pigment,  in  morphinism,  386 
Atropine,  395 

absorption,  397 

administration,  406 

and  morphine  in  hypodermatic  use, 

389 
as  preliminary  to  general  anesthesia, 

408 

elimination,  404 
in  anaphylaxis,  408 
in  diabetes,  398 
in  diseases  of  eye,  407 
in  exophthalmic  goiter,  408 
in  hyperthyroidism,  408 
in  obstipation,  407 
in  pain,  403 
in  serum  sickness,  408 
in  spasmodic  nervous  conditions,  407 
pharmacologic  action,  396-405 
poisoning  from,  405 
treatment,  406 
solubility  of,  21 
sulphate,  396 

injection,  in  ether  anesthesia,  299 
solubility  of,  21 
therapeutics,  406 

to  check  excessive  vagus  action,  408 
to  depress  sensory  nerve-endings,  407 
to  diminish  secretion,  406 
to  relax  overcontracted  smooth  muscle, 

406 

to  stimulate  respiration,  408 
tolerance,  405 
toxicology,  405 
Auricular  fibrillation,  digitalis  in,   190, 

194  _ 

from  digitalis,  170 
flutter,  digitalis  in,  189 

from  digitalis,  170 
Auriculoventricular    bundle,    action    of 

digitalis  on  circulation  through,  171 
Axilla,  sweating  of,  aluminium  chloride 

in,  536 
Axillary  sup,  231 


BACK,  pain  in,  after  ether  anesthesia,  297 
Bacterial  infections,  quinine  in,  477 
Baking  soda,  92 
Balsam  gauze,  501 

of  Peru,  501 
Balsams,  36 
Barbaloin,  133 
Barium,  212 

action  of,  212 

poisoning  from,  212 
Barnes'  medicine  dropper,  584 
Basham's  mixture,  224,  225,  538 
Bath,  bed-,  461 

cold,  461 

electric,  445 

foot-,  mustard,  77 


614 


INDEX 


Bath,  hot-air,  445 

Nauheim,  as  circulatory  stimulant,  157 

Russian,  444 

tub-,  461 

Turkish,  444 

vapor,  445 
Beck's  treatment   of    chronic    sinuses, 

532 

Bed-bath,  461 
Beebe's  serum,  562 
Beer,  317 

lager,  317 
Beeswax,  32 
Belladonna,  394,  395 

administration,  406 

constituents,  395 

dose,  395 

elimination,  404 

extracts,  396 

fluidextracts,  396 

group,  394 

pharmacologic  action,  396-405 
preparations  and  doses,  395 

leaves,  tincture,  396 

liniment,  396 

occurrence,  394 

ointment,  396 

pharmacologic  action,  396-405 

plaster,  396 

poisoning  from,  405 
treatment,  406 

therapeutics,  406 

to  depress  sensory  nerve-endings,  407 

to  diminish  secretion,  406 

tolerance,  405 

toxicology,  405 
Benedictine,  320 
Benzaconine,  231 
Benzaldehyde,  106 
Benzene,  577 
Benzin,  33 
Benzine,  576 

poisoning,  571 
Benzinum  purificatum,  33 
Benzoic  acid,  501 
Benzoin,  501 

compound  tincture  of,  133 
Benzol,  577 

in  leukemia,  577,  578 

in  lymphoid  leukemia,  578 

in  myeloid  leukemia,  578 

in  polycythemia,  578 

in  pseudoleukemia,  578 

poisoning,  577,  578 
Benzosulphinide,  68 
Benzoyl  ester  of  pseudo-tropine  chloride, 

423 
Benzoyl  -  tetramethyl-diamino-ethyl-iso- 

propylic  alcohol  chloride,  423 
Berherine,  572 
Bernard's  experiment  with  strychnine, 


Beta-eucaine  chloride,  423 

lactate,  423 
Beta-iminazolylethylamine,  567 

effect  on  circulation,  570 
Beta-naphthol,  504 
Beverages,  caffeine,  264 
Bhang,  392 
Bichloride  of  mercury  as  disinfectant, 

Si8 

dose,  520 
in  malaria,  521 
Bier's  intravenous  local  anesthesia,  425 

vein  anesthesia,  422 
Bile,  126 

salts,  126 

Biliousness,  calomel  in,  131 
Bismuth,  531 

as  antiseptic  and  disinfectant,  500 

in  gastric  irritation,  532 

in  intestinal  irritation,  532 

in  nausea,  532 

in  vomiting,  532 

milk  of,  531,  532 

poisoning,  531 

subcarbonate,  531 

subgallate,  531 

subnitrate,  531 

with  vaseline  in  chronic  sinuses  and 
tuberculous  cavities,  532 

therapeutics,  532 

treatment  for  sinuses,  532 
Bismuthum,  531 
Bites,  dog-,  caustics  for,  79 
Bitter  almond,  oil  of,  25,  426 
spirit  of,  426 
water,  426 

apple,  dose,  137 

principles,  26 
Bitters,  107 

anti-,  109 

aromatic,  108,  109 

simple,  108 
Black  snakeroot,  488 

tea,  265 

wash,  520 

Blackwater  fever,  quinine  in,  478 
Bladder,  catheterization  of,  in  strychnine 
poisoning,  279 

disinfectants,  516 
Blaud's  pills,  537 
Bleeding  from  nose,  counterirritants  for, 

78 

Blindness  from  methyl  alcohol,  355,  356 
Blister,  fly-,  77 
Blistering,  72,  73 

Blood,  capillary  flow  of,  alterations  in, 
149 

clotting  of,  effect  of  citric  acid  on,  89 

coagulation  of,  effect  of  calcium  on,  99 

effect  of  iron  on,  539 

in  arteries,  decrease  of,  causes,  149 
increase  of,  causes,  149 


INDEX 


615 


Blood  in  heart,  output  of,   influences 

affecting,  149 
transfusion  of,  225 

conditions  indicating,  226 

in  anemia,  226 

in  carbon  monoxide  poisoning,  576 

in  collapse,  226 

in  hemophilia,  227 

in  hemorrhage,  226 

in  infectious  conditions,  227 

in  malnutrition,  227 

in  prostration,  227 

in  protracted  weakness,  227 

in  sepsis,  227 

in  shock,  226 

and  collapse,  251 
Lindemann's  method,  226 
Satterlee  and  Hooker's  method,  226 
volume  of,  in  arteries,  measures  for 

increasing,  225 
measures  for  decreasing,  245 
Blood-letting,  245,  247 
Blood-pressure,  remedies   which  lower, 

231 
Blood-supply  of  brain,  154 

of  heart,  154 
Blood-vessels,  152 
Blue  ointment  as  antiseptic,  519 

pill,  131 

Body  heat,  methods  of  raising,  444 
Bone-black,  109 
Borax  as  preservative,  500 

in  epilepsy,  500 
Boric  acid  as  preservative,  500 

poisoning  from,  501 
Boroglycerin,  glycerite  of,  501 
Boro-sal,  480,  500 
Bowel  splint,  375,  376 
Brain,  blood-supply,  154 

wet,  348,  350 
Brandy,  319 
apple-,  319 
French,  319 
milk-punch,  320 
pear-,  319 
Brass  founder's  ague,  530 

shakes,  530 
Brazier's  chills,  530 
Breathing,  Cheyne-Stokes,  377 
British  gum,  29 

Brom-di-ethyl-acetyl-carbamide,  366 
Bromides,  367 
absorption,  368 

and  alkaloids,  incompatibility,  22 
dose,  367 
elimination,  369 
in  cardiac  excitability,  371 
in  convulsions,  371 
in  nervous  affections,  371 
in  pain,  371 

in  strychnine  poisoning,  279 
in  vomiting,  371 


Bromides,  pharmacologic  action,  368- 
370 

poisoning  from,  acute,  370 
chronic,  370 
treatment,  371 

rash  from,  369,  370 

therapeutics,  371 

to  lessen  nervous  irritability,  371 
sexual  hyperesthesia,  371 

to  quiet  reflexes,  371 

toxicology,  370 

Bromidrosis,  salicylic  acid  in,  483 
Bromine,  498 

waters,  147,  498 
Bromipin,  372 

in  epilepsy,  372 
Bromism,  370 
Bromoform,  372 

in  whooping-cough,  372 

poisoning  from,  372 
Bromural,  366 
Bronchi  disinfectants,  517 
Bronchial  asthma,  calcium  in,  100 
epinephrine  in,  202,  205 
oxygen  in,  580 
potassium  nitrate  in,  240 

muscles,  action  of  strychnine  on,  276 
Bronchitis,  ammonium  chloride  in,  224 

chronic,  cod-liver  oil  in,  72 
Broom,  428 
Brown  mixture,  563 
Brucine,  268 
Buckthorn,  133 
Bum  mixture,  288 
Bundle,    auriculoventricular,    action   of 

digitalis  on  circulation  through,  171 
Burns,  carbolic  acid,  alcohol  as  prevent- 
ive, 354 

Burnt  alum,  536 
Burow's  solution,  525,  536 
Butter,  30 

cocoa-,  30,  267 
Butyl  chloral  hydrate,  363 

in  trifacial  neuralgia,  363 


CACAO-BUTTER,  30,  267 
Cade,  oil  of,  35,  504 
Caffeina,  253 

citrata,  253 

effervescens,  253 
Caffeine,  252,  253 

absorption,  254 

administration,  263 

allies,  263 

as  emergency  heart  stimulant,  262 

as  stimulant,  262 

as  tonic,  262 

beverages,  264 

citrated,  253 

diuresis,  258,  260,  261 

diuretic  action,  456 


6i6 


INDEX 


Caffeine,  dose,  253 
effervescent  citrated,  253 
excretion,  258 
group,  252 
in  collapse,  262 
in  dropsy,  262 

in  night  dyspnea  of  heart  cases,  262 
pharmacologic  action,  254-261 
poisoning  from,  261 

treatment,  261,  262 
preparations  and  doses,  253 
sodio-benzoate,  253 
sod io-salicy late,  253 
strychnine  and,  comparison  of  action, 

275 

therapeutics,  262 

toxicology,  261 
Caffeol,  264 
Caff eon,  264 
Caffeotannic  acid,  264 
Calabar  bean,  436 
Calabarine,  436 
Calamine,  530 

lotion,  530 

Calcii  carbonas  praxipitatus,  97 
Calcium,  97 

absorption,  98 

carbonate,  97 

chloride,  97 

in  pleural  effusion,  100 

effect  in  intestines,  100 
on  coagulation  of  blood,  99 

glycerophosphate,  554 

hydroxide,  97 

in  angioneurotic  edema,  100 

in  bronchial  asthma,  100 

in  chilblains,  100 

in  clotting  of  milk  by  rennet,  99 

in  diabetes,  100 

in  edema,  100 

in  hay-fever,  100 

in  hemorrhage,  100 

in  nervous  diseases,  100 

in  serum-sickness,  100 

in  tetany,  98,  100 

in  transudation,  100 

lactate,  97 

permanganate,  541 

pharmacologic  action,  97-100 

poisoning,  100 

preparations,  97 

sulphide  in  acne,  124 

in  mercury  poisoning,  524 

therapeutics,  100 

Calculus,  ureteral,  papaverine  in,  390 
Calisaya,  470 
Calomel,  129 

administration,  130 

diuretic  action,  457,  521 

in  biliousness,  131 

in  croupous  laryngitis,  521 

in  sluggish  liver,  131 


Calomel  in  venereal  sores,  519 

therapeutics,  131 
Camphor,  107,  213 

absorption  of,  214 

administration,  217 

as  anti-diarrheic,  217 

as  antipyretic,  217 

as  carminative,  217 

as  cooling  application,  217 

as  counterirritant,  217 

as  stimulant  and  antiseptic  to  mucous 
membranes,  217 

chloral-,  213,  217,  359 

elimination  of,  216 

in  chloroform  collapse,  309 

in  colds,  217 

in  collapse,  217 

in  diarrhea,  217 

in  fever,  217 

in  hysteric  conditions,  217 

in  nervous  instability,  217 

in  pneumonia,  217 

in  shock,  217 

liniment,  213 

local  uses,  217 

menthol-,  213,  217 

monobromated,  213 

pharmacologic  action,  213-216 

poisoning  from,  216 

preparations  and  doses,  213 

spirit  of,  dose,  213 

therapeutics,  217 

toxicology,  216 

water,  dose,  213 
Camphora,  213 

monobromata,  213 
Camphorated  oil,  213 

tincture  of  opium,  dose,  373 
Camphoric  acid,  412 

dose,  412 
Canadine,  572 
Cane-sugar,  27,  69 

in  leucorrhea,  69 
Cannabinine,  392 
Cannabinol,  392 
Cannabis,  392 

constituents,  392 

extract,  dose,  392 

fluidextract,  dose,  392 

pharmacologic  action,  392 

preparations  and  doses,  392 

saliva,  392 

therapeutics,  393 
Cantharides,  77 
Cantharis,  77 

vesicatoria,  77 
Capillary  flow  of  blood,  alterations  in. 

149 
Carbo  animalis,  109 

ligni,  IOQ 
Carbohydrates  and   water,  preliminary 

feeding  with,  in  ether  anesthesia,  299 


INDEX 


617 


Carbolic  acid,  504.     See  also  Phenol. 
burns,  alcohol  as  preventive,  354 
Carbon  dioxide  in  collapse,  252 
in  shock,  252 
therapeutics,  79 
monoxide,  574 

poisoning  from,  574 
acute,  575 
chronic,  575 
oxygen  in,  580 
transfusion  of  blood  in,  576 
treatment,  576 

Cardamom,  compound  tincture,  107 
Cardiac  depressants,  231 

excitability,  bromides  in,  371 
insufficiency,  edema  of,  diuretics  in, 

456 

muscle,  action  of  digitalis  on  circula- 
tion through,  1 66 
Carica  papaya,  85 
Carminatives,  102 
as  antemetics,  112 
as  anthelmintics,  105 
as  anti-asthmatics,  105 
as  anticolics,  104 
as  antihysterics,  105 
as  antirheumatics,  105 
as  antiseptics,  105 

and  anesthetics,  105 
as  bronchial  stimulants,  105 
as  correctives,  105 
as  counterirritants,  105 
as  diuretics,  105 
as  emmenagogues,  105 
as  odors  and  flavors,  104 
as  stimulants  in  chronic  skin  diseases, 

105 

to  growth  of  hair,  105 
to  mucous  membranes  of  nose  and 

throat,  105 

as  urinary  antiseptics,  105 
compound  tinctures,  107 
doses,  107 
elimination  of,  104 
elixirs,  106 
fluidextracts,  107 
in  leprosy,  105 
in  tympanites,  105 
pharmacologic  action,  102-104 
poisoning  from,  104 
preparations,  106 
simple  aromatic  tinctures,  107 
spirits,  106 
therapeutics,  104 
tinctures,  compound,  107 

simple  aromatic,  107 
toxicology,  104 
volatile  oils  of,  106 
waters,  106 
Cascara  sagrada,  133 
Castile  soap,  30,  31,  127 
Castor  oil,  30,  127 


Castor  oil,  administration,  128 

therapeutics,  128 
Castor-lax,  128 
Cataplasma,  definition,  42 

kaolini,  76,  in 
Cathartic  enema,  143 

as  softening  agent,  143 
to  soften  feces,  144 
measures,  122 
apocodeine,  124 
cereals,  123 
drugs,  124 
exercises,  122 
fixed  oils,  127 
foods,  123 
fruits,  124 
glycerin,  127 
habit  formation,  122 
massage,  123 
mechanical  agents  to  give  bulk  and 

soft  consistency  to  feces,  124 
physostigmine  salicylate,  124 
pituitary  extract,  124 
response  to  desire  to  defecate,  122 
salads,  123 
soaps,  127 
vegetables,  123 
water,  124 
mercurials,  129 
pills,  compound,  131,  133,  137 

vegetable,  137 
Cathartics,  119 

acting  by  selective  affinity,  124 
cramp  from,  121 
griping  from,  121 
saline,  137 
doses,  138 

in  constipation,  objections,  143 
Moreau's  loop  and,  141 
pharmacologic  action,  139-142 
preparations,  138 
therapeutics,  142 
time  to  give,  56 
Catheterization  of  bladder  in  strychnine 

poisoning,  279 
Caustic  acids,  78 
alkalies,  78,  91 
lunar,  533 
metallic  salts,  78 
Caustics,  78 
therapeutics,  79 
toxicology,  79 
Cauterize,  79 
Cautions,  63 

Cecum  as  factor  in  defecation,  120 
Cells,  effect  of  drugs  on,  57 
Cellulitis,  magnesium  sulphate  in,  315 
Central  emetic,  in 
nervous  stimulants,  252 

system,  remedies  acting  on,  252 

which  depress,  282 
sedatives  as  antemetics,  112 


6i8 


INDEX 


Cephaeline,  564 
Cephaelis  acuminata,  564 

ipecacuanha,  564 
Cera  alba,  32 

flava,  32 

Cerate,  definition,  42 
Ceratum,  definition,  42 
Cereals  as  cathartic  measure,  123 
Cerebral  circulation,    adequate,    main- 
tenance of,  155 

congestion,  counterirritants  for,  78 

depression  from  hypnotic  drugs,  358 
Cerebrospinal  fluid,  effect  of  pituitary 
extract  on,  210 

syphilis,  neosalvarsan  in,  550 

salvarsan  in,  550 
Cerium,  532 

in  nausea,  532 

in  vomiting,  532 

oxalate,  532 
Cetaceum,  32 
Cetyl  palmitate,  32 
Cevadilline,  237 
Cevadine,  236 

pharmacologic  action,  237 
Chalk,  drop-,  97 

mixture,  97 

powder,  compound,  97 

precipitated,  97 

prepared,  97 
Chalybeate  waters,  147 
Chamomillin,  26 
Charcoal,  109 

animal,  109 
purified,  109 

wood-,  109,  no 
Charta,  definition,  42 

sinapis,  77 
Chartreuse,  320 
Chemic  incompatibility.  603 

percentage  liquid,  38 
Chemical  relationships  ot  phenol  group 

of  disinfectants,  502 
Chemistry,  pharmaceutic,  18 
Chenopodium,  oil  of,  for  hookworms,  117 
for  pin-worms,  1 1 8 
for  round-worms,  118 
for  tape-worms,  118 
for  whip- worms,  1 1 8 
poisoning  from,  118 
Cherry,  wild,  fluidextract  of,  426 
infusion  of,  426 
syrup  of,  426 
Cherry-gum,  29 
Chewing-tobacco,  429 
Cheyne-Stokes'  respiration,  377 
Chilblains,  calcium  in,  100 
Children,  doses  for,  48 
Chills,  brazier's,  530 

spelter,  530 

zinc,  530 
Chloral  hydrate,  245,  358 


Chloral  hydrate,  absorption,  359 

administration,  363 

as  circulatory  depressant,  363 

as  hypnotic,  362 

as  motor  depressant,  363 

cautions,  363 

contraindications,  363 

elimination,  361 

in  obstetrics,  363 

in  pain,  363 

in  strychnine  poisoning,  279 

in  toothache,  362 

pharmacologic  action,  359-362 

poisoning  from,  acute,  362 
chronic,  362 

therapeutics,  362 

toxicology,  362 

untoward  effects,  362 
Chloralamide,  363 
Chloral-camphor,  213,  217,  359 
Chloralformamidum,  363 
Chloralism,  362 
Chloralum  hydratum,  358 
Chloramins,  494 
Chlorazene,  498 
Chlorbutanol,  363,  424 
Chloretone,  363,  424 
as  preliminary  to  ether   anesthesia, 

364 

in  seasickness,  364 
Chloride  of  ammonia,  223 

of  lime,  494 
Chlorinated  lime,  494 
Chlorine,  494 
water,  494 
Chloroform,  289 
and    epinephrine,  simultaneous    use, 

effects,  204 
anesthesia,  292,  300 

advantages,  300 

camphor  in,  309 

collapse  in,  amyl  nitrite  in,  245 
treatment,  309 

contraindications,  304 

dangers,  301-304 

delayed  poisoning  from,  302 

intravenous,  307 

phagocytic   activity   of   leukocytes 
after,  305 

preventive  measures  in,  304 
as  antemetic,  292 
as  antihysteric,  292 
as  carminative,  292 
as  rubefacient,  292 
dose,  289 
elimination,  291 
for  tape- worms,  119 
habit,  292 
in  colic,  292 
in  flatulence,  292 
in  pain,  202 
in  toothache,  292 


INDEX 


6lQ 


Chloroform  in  vomiting,  292 

inhalations  in  strychnine   poisoning, 
279 

liniment,  213,  289 

pharmacologic  action,  289-292 

poisoning,  delayed,  302 

preliminary  administration,  in  ether 
anesthesia,  298 

preparations  and  doses,  289 

spirit,  dose,  289 

therapeutics,  292 

water,  dose,  289 
Chloroform-acetone,  363 
Chloroformum,  289 
Chlorosis,  iron  in,  540 
Chlumsky's  solution,  509 
Chocolate,  253,  264,  267 
Cholagogue,  122 
Cholera  drops,  Sun,  213 

kaolin  in,  no 

mixture,  Sun,  146 

purified  animal  charcoal  in,  no 

saline  infusion  in,  230 
Cholesterol,  32 

in  anemia,  32 

in  pernicious  anemia,  32 
Choline,  567 
Chorea,  antipyrine  in,  469 

magnesium  sulphate  in,  315 

salicylic  acid  in,  483 
Chrome  holes,  79 
Chromium  trioxide,  79 
Chrysarobin,  26,  81 

in  psoriasis,  81 

Churchill's  tincture  of  iodine,  499 
Cider,  apple,  318 

pear,  318 
Cimicifuga,  488 

in  gout,  488 

in  rheumatism,  488 
Cinchona,  470 

administration,  478 

compound  tincture  of,  109 
dose,  470 

constituents,  470 

fluidextract,  dose,  470 

pharmacologic  action,  471-476 

preparations  and  doses,  470 

rubra,  470 

tincture,  dose,  470 
Cinchonidine,  470 

sulphate,  471 
Cinchonine,  470 

sulphate,  471 
Cinchonism,  476 
Cinnaldehyde,  106 
Cinnamic  acid,  501 
Cinnamomum  camphora,  213 
Cinnamon,  oil  of,  504 
Cinnamyl-cocaine,  412 
Circulation,   cerebral,   adequate,   main- 
tenance of,  155 


Circulation,  coronary,  151 

adequate  maintenance  of,  155 
physiology  of,  148 
pulmonary,  155 
remedies  whose  chief  action  is  upon, 

148 
Circulatory  organs,  functions,  148 

stimulants,  157 

Citrate  of  iron  and  quinine,  538 
and  strychnine,  538 

dose,  269 

Citra'ted  caffeine,  253 
effervescent,  253 
Citrates,  90 
Citric  acid,  88,  90 

effect  of,  on  clotting  of  blood,  89 
in  typhoid  fever,  89 
Citrine  ointment  as  antiseptic,  519 
Citrophen,  463 
Clark's  rule  for  dosage,  48 
Clay  poultice,  76 
Clitocybe  illudens,  443 
Clotting  of  blood,  effect  of  citric  acid  on, 

89 

of  milk  by  rennet,  calcium  in,  99 
Cloves,  oil  of,  504 
Coagulation  of  blood,  effect  of  calcium 

on,  99 

of  citric  acid  on,  89 
Coca,  412 

wine  of,  therapeutics,  420 
Cocaine,  412 

as  diagnostic  agent  in  tic,  421 
excretion,  418 
habit,  420 

treatment,  420 
hydrochloride,  412 

as  anesthetic,  420 

in  collapse  from  narcotic  drugs,  422 
in  diseases  of  anus,  421 
of  esophagus,  421 
of  nose,  420 
of  stomach,  421 
of  throat,  421 
in  itching  of  vulva,  421 
in  spasm  of  urethra,  421 
in  vaginismus,  421 
intravenous  anesthesia  with,  422 
pharmacologic  action,  413-419 
poisoning,  419 

Magnan's  sign  in,  419 
treatment,  419 

spinal  anesthesia  with,  414,  415,  421 
substitutes,  422 
therapeutics,  420 
toxicology,  419 
untoward  effects,  418 
Cocktail,  320 
Cocoa,  30,  268 

nibs,  267 

Cocoa-butter,  30,  267 
Cocoanut  oil,  30 


62O 


INDEX 


Codeine,  373,  388 
dose,  373 
in  cough,  388 
in  diabetes,  387,  388 
in  pain,  388 
phosphate,  373 
sulphate,  373 
Cod-liver  oil,  30,  71 

in  chronic  bronchitis,  72 
in  malnutrition,  72 
in  poor  nutrition, 72 
in  rickets,  72 
in  spasmophilia,  72 
in  tuberculosis,  72 
preparations  and  doses,  72 
therapeutics,  72 
Coffee,  253,  264 
habit,  266 

pharmacologic  action,  265,266 
tolerance,  266 
Cognac,  319 
Colchicine,  dose,  487 
Colchicum,  486 
autumnale,  486 
in  gout,  487 

pharmacologic  action,  487 
poisoning  from,  487 
preparations  and  doses,  487 
Cold,  76,  461 
as  preservatives,  492 
bath,  461 
quinine  in,  477 
Cold-pack,  461 
Colds,  camphor  in,  217 
Colic,  chloroform  in,  292 
lead,  526 
painter's,  526 
Colitis,  amebic,  quinine  in,  476 

silver  nitrate  in,  534 
Collapse,  248 
caffeine  in,  262 
camphor  in,  217 
carbon  dioxide  in,  252 
counterirritants  for,  78 
epinephrine  in,  206,  251 
from  narcotic  drugs,  cocaine  in,  422 
in  anesthesia,  oxygen  in,  580 

treatment,  309 
in  chloroform  anesthesia,  amyl  nitrite 

in,  245 

camphor  in,  309 
treatment,  309 
in  ether  anesthesia,  296 
saline  infusion  in,  309 
treatment,  309 
massage  of  heart  in,  251 
mechanical  measures  in,  225,  251 
mild  and  transitory,  250 
moderate  degree,  250 
pituitary'  extract  in,  251 
respiratory  paralysis  and,  249 
saline  infusion  in,  230 


Collapse,  severe,  250 
stimulants  in,  251 
symptoms,  250 

transfusion  of  blood  in,  226,  251 
treatment,  250 

prophylactic,  250 
Collargol,  534 
Collodion,  definition,  41 
Collodium,  definition,  41 
Colloid  goiter,  iodides  in,  559 

thyroid  gland  in,  562 
Colloidal  silver,  534 
Colocynth,  compound  extract  of,  133, 

137 

dose,  137 
dose,  137 

Cologne  spirit,  316 
Colon  as  factor  in  defecation,  120 

irrigations  of  saline  solution,  145 
Colonic  anesthesia,  306 
Colors  for  prescription,  586 
Coma,  282 

Compensation  of  heart,  156 
failure,  156,  157 

digitalis  in,  194 
threatened  failure,  157 
Compound  cathartic  pills,  131,  133,  137 
chalk  powder,  97 
cresol  solution,  503 
extract  of  colocynth,  133,  137 

dose,  137 

jalap  powder,  dose,  137 
laxative  pills,  dose,  269 
licorice  mixture,  563 

powder,  552 
morphine  powder,  374 
pharmaceutic  preparations,  39 
rhubarb  pills,  133 
solution  of  iodine,  555 
spirit  of  ether,  dose,  284 
of  juniper,  319 
of  orange,  320 
syrup  of  hypophosphites,  554 

dose,  269 
of  squill,  1 60,  552 

as  expectorant,  564 
tincture  of  benzoin,  133 
of  cardamom,  107 
of  cinchona,  109 

dose,  470 

of  gambir,  114 

of  gentian,  109 

of  lavender,  107 

Compressed  tablets,  587 

definition,  41 
Confectio,  definition,  42 
Confection,  definition,  42 
Congestion,  cerebral,  counterirritants  for, 

78 

counterirritants  for,  78 
Conium,  427 
fluidextract,  427 


INDEX 


621 


Conjunctions,  Latin,  591 
Conjunctival  argyria,  535 
Conjunctivitis  after  ether  anesthesia,  298 

copper  sulphate  in,  529 

zinc  sulphate  in,  530 
Connective-tissue  changes  in  heart  and 

arteries  from  epinephrine,  201 
Constipation,  119 

chronic,  hormonal  in,  85 

saline  cathartics  in,  objections,  143 
Contraction  of  peripheral  arteries  from 

digitalis,  178 
Contraindications,  63 
Convalescence,  alcohol  in,  354 
Convallamarin,  160 
Convallaria,  160,  184 

majalis,  160 
Convallarin,  160 
Convulsions,  bromides  in,  371 

magnesium  sulphate  in,  315 
Convulsive  center,  action  of  digitalis  on, 

183 

reflexes,  272 

f rom  strychnine,  272 
Coordinated  reflexes,  272 
Copper,  529 

aceto-arsenite  of,  546 

as  antiseptic  and  disinfectant,  500 

poisoning,  529 

therapeutics,  529 
Copperas  as  disinfectant,  536 
Cordials,  320 
Cornea,  ulcer  of,  ethylhydrocupreine  in, 

479 

Corns,  salicylic  acid  for,  483 
Cornstarch,  28 

Coronary    arteries,    constriction,    from 
digitalis,  176 

circulation,  151 

adequate,  maintenance  of,  155 
Corrosive  sublimate  as  disinfectant,  518 
Cotarnine,  23 

hyclrochioride,  574 
Cottonseed  oil,  30 
Cough,  codeine  in,  388 

lactucarium  lozenges  in,  393 

morphine  in,  378,  387 

papaverine  in,  390 

strychnine  in,  276 
Counterirritants,  72 

as  antemetics,  112 

cautions,  78 

measures,  75 

mode  of  action,  73 

therapeutics  of,  78 
Counterirritation,  72 
Cowling's  rule  for  dosage,  49,  595 
Coxe's  hive  syrup,  552 

as  expectorant,  564 
Cramp  from  cathartics,  121 
Cream  of  tartar,  101,  102 
dose,  138 


Crede's  method  of  prophylaxis  against 

gonorrheal  ophthalmia,  533 
Creme  de  menthe,  320 
Cr ernes,  320 
Creolin,  503 
Creosote,  35,  503 

carbonate,  503 
Cresol,  503 

solution,  compound,  503 
Creta  praeparata,  97 
Cretinism,  thyroid  gland  in,  562 
Crile's  anoci-association,  249,  250 

pneumatic  suit  in  shock,  225,  251 
Croton  oil,  30,  136 

dose,  137 

Crotonic  acid,  136 
Croup,  mercury  subsulphate  in,  521 
Croupous  laryngitis,  calomel  in,  521 
Crude  drugs,  19 
Crystalline  gratus  strophanthin,  161 

elimination,  183 
Cumulative  poison,  47 
Cupping,  dry-,  76,  247 

wet-,  247 
Cuprum,  529 
Curare,  427 
Curarine,  427 

Cutaneous  arteries,  action  of  digitalis  on 
circulation  through,  180 

arterioles,  caliber,  154 
Cyanides,  426 

pharmacologic  action,  426 

poisoning  from,  426 
treatment,  427 

preparations,  426 
Cyanosis  in  anesthesia,  treatment,  309 

oxygen  in,  580 
Cycloplegic,  definition,  403 
Cymarin,  160 
Cystogen,  512 


D  AKIN-CARREL  treatment,  495 
Dakin's  solution,  preparation,  495,  496 

Daufresne's  technic,  495 
test  for  alkalinity,  497 
titration,  497 

Dale's  vasomotor  reversal,  569 
Dating  prescription,  582 
Datura  stramonium,  394 
Daufresne's   technic  for  preparation  of 

Dakin's  solution,  495 
Dawson's    solution   for  saline  infusion, 

227 
Deadly  agaric,  443 

nightshade,  394 
Deafness  from  smoking,  435 
Death's-head  fungus,  442,  443 
Decapsulation   of   kidneys    in   mercury 

poisoning,  524 
Decoction,  definition,  40 
Decoctum,  definition,  40 


622 


INDEX 


Defecate,   response    to    desire    to,    as 

cathartic  measure,  122 
Defecation,  mechanical  factors  of,  120 
cecum  and  colon,  120 
small  intestine,  120 
Degeneration,  fatty,  of  heart,    digitalis 

in, 192 

Dehydrated  alcohol,  316 
Delayed  chloroform  poisoning,  302 
Delirium  tremens,  348 
ergot  in,  348,  572 
hyoscine  in,  409 
lumbar  puncture  in,  349 
magnesium  sulphate  in,  315 
treatment,  348 
Delphinium,  236 
Demulcents,  67 
Denatured  alcohol,  316 
Deodorant,  488 
Deodorized  alcohol,  316 

opium,  373 
Deodorizer,  488 
Deodorizers  used  as  gas,  514 
in  dry  form,  514 
in  solution,  514 
Deoxidizers,  493 
Depressants,  cardiac,  231 
Depression.  57 
Desiccated  hypophysis,  207 

thyroid  glands,  560 
Dextrin,  29 
Dextro-glucose,  69 
Dextro-hyoscyamine,  395 
Dextrose,  69 

diuretic  action,  455 
Diabetes,  alcohol  in,  343 

antipyrine  in,  469 

atropine  in,  398 

calcium  in,  100 

codeine  in,  387,  388 

glycerin  in,  31 

insipidus,  ergot  in,  572 
pituitary  extract  in,  210 

lactic  acid  in,  90 

morphine  in,  387 

opium  in,  387 

salicylic  acid  in,  484 

sodium  bicarbonate  in,  95 
Di-acetyl  morphine,  390 
Diacetyltannin,  115 
Diamino-dihydroxy-arsenobenzol     dihy- 

drochloride,  542 
Diaphoresis,  443 

character  of  sweat  in,  447 

in  chronic  rheumatism,  450 

in  nephritis,  448 

in  sickness,  448 

in  uremia,  448 

measures  to  produce,  443,  444 

relation  of,  to  nitrogenous  excretion, 

447 
Diaphoretics,  443 


Diaphoretics,  administration,  449 

therapeutics,  449 

to  assist  kidneys,  449 

to  hasten  outbreak  of  rash,  450 

to  lessen  congestion  of  internal  eye,  449 

of  middle  and  internal  ear,  449 
edema  and  promote  absorption  of 

dropsical  effusions,  449 
obesity,  449 

to  lower  temperature,  449 

to  overcome  chill  or  cold,  449 
Diarrhea,  camphor  in,  217 

kaolin  in,  no 

mixture,  Squibb's,  213 

remedies  for,  146 
Diarsenol,  542 
Diaspirin,  485 
Diastase,  84 
Dibothriocephalus  latus,  remedies  for, 

119 

Dichloramin-T,  498 

Diet,  salt-free,  prolonged,  results  of,  93 
Dietetic  measures,  18 
Di-ethyl  barbituric  acid,  365 

malonyl  urea,  365 

morphine  chloride,  424 
Diethylene-diamine,  488 
Diffusion,  228 
Digalen,  158 

dose,  158 

Digestive  ferments,  81 
Digifolin,  159 
Digipuratum,  158 
Digitalein,  158 
Digitalin,  158 

dose,  158 
Digitalis,  157 

absorption  of,  164 

action  of,  on  nutrition  of  heart,  177 
on  recuperative  power  of  heart,  1 77 

allies,  159 

elimination,  183 

arhythmia  from,  166 

auricular  fibrillation  from,  170 

change  in  electrocardiograms  from,  177 

complete  heart-block  from,  172 

constituents,  157 

constriction  of  coronary  arteries  from, 
176 

contraction  of  peripheral  arteries  from, 
178 

diuresis,  181 

doses,  158 

elimination  of,  183 

fluiclextract  of,  dose,  159 

group, i 60 

heart-block  from,  172 

in  aneurysm  of  aorta,  195 

in  aortic  insufficiency,  193 
stenosis,  194 

in  aortitis,  195 

in  arteriosclerosis,  195 


INDEX 


623 


Digitalis  in  auricular  fibrillation,   100, 
194 

flutter,  189 

in  dilatation  of  heart,  192 
in  dropsy,  181,  182 
in  edema,  181,  182 
in  failure  of  compensation    of    heart, 

194 

in  fatty  degeneration  of  heart,  192 
in  heart-block,  189 
in  high  arterial  pressure,  191 
in  infectious  diseases,-  195 
in  mitral  insufficiency,  193 

stenosis,  194 

in  muscular  inability  of  heart  asso- 
ciated with  valvular  lesion,  192 
in  myocarditis,  192 
in  normal  rhythm  of  heart,  191 
in  paroxysmal  tachycardia,  189 
in  pneumonia,  166,  195 
in  premature  contractions  of  heart,  189 
in  pulsus  alternans,  189 
in  sinus  arhythmia,  189 
in  venous  engorgement,  181 
in  water-retention,  182 
incipient  heart-block  from,  172 
increased  arterial  pressure  from,  179 
indications,  194 
influence  of  conditions  of  arteries  on 

usefulness  of,  192 
of  heart  on  usefulness  of,  192 
infusion  of,  dose,  158,  159 
local  action,  162 
partial  heart-block  from,  172 
permanency  of  preparations,  161 
persistence  of  effect,  187 
pharmacologic  action,  162-184 
phasic  arhythmia  from,  176 
poisoning  from,  184 
cumulative,  186 
overwhelming  dose,  184 
single  large  dose  by  mouth,  185 
symptoms,  186 
treatment,  188 
preparations  and  doses,  158 

standardization    and    permanency, 

161 

pulsus  alternans  from,  176 
purpurea,  157 

retention  of  urine  from,  181 
series,  160 

slowing  of  heart  from,  165 
standardization   and   permanency   of 

preparations,  161 
suppression  of  urine  from,  181 
therapeutics,  188 

summary,  195 
tincture  of,  dose,  158,  159 
toxicology,  184 
use  as  determined  by  rhythm  and  rate 

of  heart,  IQI 
value  of,  183 


Digitalosmin,  158 
Digitonin,  20,  158 
Digitoxin,  158 

dose,  158 

Dihydrpxyphthalophenone,  134 
Dilatation  of  arteries,  153 

of  heart,  156 
digitalis  in,  192 

of  veins,  154 
Dilators,  arterial,  239 
Dilute  nitric  acid,  therapeutics,  88 

nitrohydrochloric   acid,   therapeutics, 
88 

phosphoric  acid,  therapeutics,  88 
Diluted  acetic  acid,  89 

alcohol,  316 

hydriodic  acid,  555 

nitrohydrochloric  acid,  86 
Dimazon  ointment,  80 
Dimethyl  xanthines,  252 
Di-methyl-amino-benzoyl  pentanol  chlo- 
ride, 423 
Dimethyl  -  dimethyl  -  amino  -  pyrazolon, 

462 

Dimethyl-ethyl  carbinol,  366 
Dionine,  391,  424 
Diphtheria,  kaolin  in,  no 
Diplosal,  485 
Dipropaesin,  424 
Dipsomania,  346 
Direct  local  action,  52 
Disease,  nature  of,  dose  and,  51 

resistance  to,  alcohol  and,  352 
Disinfectants,  488 

bladder,  516 

bronchi,  517 

classification,  491 
therapeutic,  514 

eye,  516 

for  dressings,  515 

for  local  use  about  body,  516 

for  obstetrician's  hands,  516 

for  skin,  516 

for  surgeon's  hands,  516 

for  surgical  instruments,  515 
supplies,  515 

for  utensils,  515 

in  skin  diseases,  516 

intestinal,  517 

larynx,  517 

mouth,  516 

nose,  516 

open  wounds,  517 

rectum,  517 

respiratory,  517 

stomach,  517 

tests  for  value,  489 

therapeutic  classification,  514 

throat,  516 

to  be  given  by  mouth,  517 

urethra,  516 

urinary  tract,  517 


624 


INDEX 


Disinfectants  used  as  gas,  514 
in  dry  form,  514 
in  solution,  514 
vagina,  516 
Disinfection   of   wounds,    Dakin-Carrel 

treatment,  495 
terminal,  515 
Dispensatory,  47 
Distilled  liquors,  318 

from    fermented    saccharine    fruit- 
juices,  319 

from  malt  liquors,  318 
medicinal  dose,  321 
Diuresis,  450 

caffeine,  258,  260,  261 
digitalis,  181 
in  acute  nephritis,  460 
in  chronic  nephritis,  460 
production  of,  453 
by  caffeine,  456 
by  calomel,  457 
by  dextrose,  455 
by  increasing    blood-flow    through 

kidneys,  453 
by  inorganic  salts,  455 
by    lowering    osmotic    pressure    of 

blood, 454 
by  measures  which  decrease  tubular 

absorption,  456 
which  increase  glomerular  fluid, 

453 
tubular  secretion,  456 

by  organic  salts,  455 

by  theobromine,  456 

by  theocine,  456 

by  theophylline,  456 

by  urea,  455 

by  water,  455 
secretion  threshold  in,  457 
therapeutic  production,  453 
therapeutics,  459 
to  cause  removal  of  dropsy  and  edema, 

459 

to  promote  elimination  of  toxins,  459 
Diuretics,  450 

in  edema  of  cardiac  insufficiency,  456 

in  nephritis,  456 

therapeutics,  459 

to  cause  removal  of  dropsy  and  edema, 

459 

to  promote  elimination  of  toxins,  459 
Diuretin,  264 
Dobell's  solution,  505 
Dogbane,  160 
Dog-bites,  caustics  for,  79 
Donovan's  solution,  541 
Dormiol,  366 
Dosage,  47 

Clark's  rule,  48 

Cowling's  rule  for,  49,  595 

for  children,  48 

Fried's  rule  for,  49 


Dosage,  Young's  rule  for,  49 
Dose,  age  and,  48 

body  weight  and,  48 

channel  of  administration  and,  51 

factors  which  modify,  48 

for  children,  48 

form  of  remedy  and,  51 

frequency  of  administration  and,  52 

idiosyncrasy  and,  50 

maximum,  47 

minimum,  47 

nature  of  disease  and,  51 

object  of  medication  and,  51 

occupation  and,  50 

prevous  habits  and,  50 

race  and,  50 

repeated,  47 

sex  and,  50 

single,  47 

susceptibility  and,  50 

temperature  and,  50 

therapeutic,  47 

time  of  administration  and,  52 

toleration  and,  50 

toxic,  47 

weight  and,  48 
Dover's  powder,  dose,  373,  564 

in  cold,  449 
Draper's  method  of  intraspinous  use  of 

salvarsan,  550 
Drastics,  135 

cautions,  136 

doses,  137 

pharmacologic  action,  135 

poisoning  from,  135 

preparations,  137 

therapeutics,  136 

uses,  135 

Dressings,  disinfectants  for,  515 
Drink,  Imperial,  88 
Drinkers,  periodic,  346 

steady,  346 
Drip-sheet,  461 
Drop-chalk,  97 
Drops,  584 
Dropsy,  caffeine  in,  262 

digitalis  in,  181,  182 

elaterin  in,  136 
Drugs,  active  constituents,  19 

administration  of,  52.  See  also  Admin- 
istration. 

as  cathartic  measures,  124 

assayed,  44 

crude,  19 

effect  of,  on  cells,  57 

how  much  to  learn  about,  61 

irritant,  time  to  give,  56 

organic,  constituents  of,  19 
active,  19,  20 
inert,  19 

selective,  56 

sites  and  modes  of  action,  56 


INDEX 


625 


Drugs,  useful,  book  of,  47 

varieties,  19 
Drunkenness,  344 
after-effects,  345 
treatment,  345 
Dry-cupping,  76,  247 
Dry  wine,  318 

Dwarf  tape- worms,  remedies  for,  119 
Dwarfism,  anterior  lobe  extract  in,  211 
Dysentery,  amebic,  calcium  permangan- 
ate in,  541 
emetine  in,  566 
ipecac  in,  566 
quinine  in,  478 
kaolin  in,  no 

purified  animal  charcoal  in,  no 
Dyspnea,  Hoffmann's  anodyne  in,  288 
Dystrophia    adiposo-genitalis,    anterior 
lobe  extract  in,  211 


EARLY-BIRD  mixture,  poisoning  from,  119 

Earth,  fullers',  no 

Eau  de  Javelle,  494 

Ecgonine,  412,  413 

Eclampsia,  veratrum  in,  238 

Edema,  angioneurotic,  calcium  in,  100 

calcium  in,  100 

digitalis  in,  181,  182 

of  cardiac  insufficiency,  diuretics  in, 
456 

of  lungs,  acute  paroxysmal,  morphine 

in, 387 
oxygen  in, 580 

relation  of,  to  salt  retention,  93 
Effervescent  citrated  caffeine,  253 

salt,  granular  definition,  42 
Effervescing  mineral  waters,  146 

potassium  citrate,  dose,  138 

sodium  phosphate,  dose,  138 
Egg-albumin  tannate,  115 
Egg-nog,  320 
Ehrlich's  "606,"  542 
Elaterin,  26,  136 

dose,  137 

in  dropsy,  136 
Electric  bath,  445 
Electrocardiograms,    change    in,    from 

digitalis,  177 
Eleopten, 35 
Elixir,  aromatic,  106,  320 

aromaticum,  106,  320 

definition,  40 

glycyrrhizae,  106,  320 

of  phosphates  of  iron,   quinine,  and 

strychnine,  537 
dose,  269 
Elixirs,  319 

official,  320 

pharmaceutic,  320 
Emetics,  ni 

central,  IIT 

40 


Emetics,  reflex,  in 

therapeutics,  112 
Emetine,  564 

hydrochloride,  564 

in  amebic  dysentery,  566 

in  pyorrhea  alveolaris,  566 

pharmacologic  action,  564,  565 
Emmenagogues,  567 
Emodins,  131 
Emollients,  67 
Empiric  therapeutics,  58 
Emplastrum,  definition,  42 
Empyreumatic  oils,  34,  35 
Emulsin,  25,  27 
Emulsion,  artificial,  40 

definition,  40 

natural,  40 

Emulsum,  definition,  40 
Encephalopathy,  lead,  527 
Enema,  55,  143 

cathartic,  143 

as  softening  agent,  143 
to  soften  feces,  144 

evacuating,  144 

nutritive,  144 

of  salt  solution,  230 

to  induce  expulsion  of  gas,  144 
Engorgement,  venous,  digitalis  in,  181 
Enteric  pills,  36,  586 
;  Entoloma  sinuatum,  443 
Enuresis  nocturna,  ergot  in,  572 
Enzymes,  27 
Epididymitis,   magnesium  sulphate  in, 

3.IS 
Epilepsy,  borax  in,  500 

bromipin  in,  372 
Epinephrine,  196 

absorption  of,  198 

and     chloroform,    simultaneous    use, 
effects,  204 

connective-tissue  changes  in  heart  and 
arteries  from,  201 

dangers,  206 

elimination  of,  204 

hydrochloride,  solution  of,  dose,  197 

hypodermic  injection,  205 

in  Addison's  disease,  205 

in  anterior  poliomyelitis,  205 

in  bronchial  asthma,  202,  205 

in  collapse,  206,  251 

in  hay-fever,  205 

in  hemorrhage,  205 

in  infantile  paralysis,  205 

in  itching  of  vulva,  205 

in  nose-bleed,  205 

in  postpartum  hemorrhage,  205 

in  shock,  206,  251 

increased  force  of  heart  from,  200 

intramuscular  injection  of,  effects  of, 
199 

intravenous  administration,  206 
dangers,  206 


626 


INDEX 


Epinephrine,  intravenous  injection,  ef- 
fects, 199 

local  use,  dangers,  206 
metabolism  of,  204 
pharmacologic  action,  197-204 
poisoning  from,  204 
preparations  and  doses,  197 
slowing  of  heart  from,  200 
subcutaneous  injection,  effects,  199 
therapeutics,  205 
to  check  anaphylactic  shock,  205 
to  prevent  local  hemorrhage,  205 
to  prolong  local  anesthesia,  205 
to  shrink  mucous  membrane,  205 
toxicology,  204 
vasoconstriction  from,  199 
Epispastic,  72 

Epistaxis,  counterirritants  for,  78 
Epsom  salt  as  anesthetic,  313 
intraspinal  method,  314 
intravenous  use,  314 
Meltzer's  theory,  314 

dose,  138 

in  arthritis,  315 

in  cellulitis,  315 

in  chorea,  315 

in  convulsions,  315 

in  delirium  tremens,  315 

in  epididymitis,  315 

in  erysipelas,  315 

in  pain,  315 

in  spasmophilia,  315 

in  tetanus,  314 
Ergot,  567 

constituents,  567 

deterioration,  568 

dose,  568 

extract,  dose,  568 

fluidextract,  dose,  568 

in  delirium  tremens,  348,  572 

in  diabetes  insipidus,  572 

in  enuresis  nocturna,  572 

in  menorrhagia,  572 

in  subinvolution  of  uterus,  572 

pharmacologic  action,  568-570 

poisoning,  571 

chronic,  571 

preparations  and  doses,  568 
standardization,  568 
therapeutic?,  571 
to   prevent   postpartum   hemorrhage, 

57i 

toxicology,  571 
Ergota,  567 
Ergotine,  567 
Ergotinic  acid,  567 
Ergotism,  571 

gangrene  in,  571 

nervous  type,  571 
F.rgotoxine,  567 

effect  on  circulation,  569 

phosphate,  dose,  568 


Eriodictyon,  109,  425 

Erysipelas,  magnesium  sulphate  in,  315 

Erythrol  tetranitrate,  240 

effect,  242 
Erythroxylon  coca,  412 

truxillense,  412 
Escharotics,  78 
Eseridine,  436 
Eserine,  436 

Esophagus,  diseases  of,  cocaine  in,  421 
Essences  of  plants,  34 
Essential  oils,  34 
Ether,  284 

absorption,  285 
anesthesia,  292 

administration,  general  remarks,  305 

of  sodium  bicarbonate,  299 
after-effects,  297 

chloretone  as  preliminary  to,  364 
collapse  in,  296 

saline  infusion  in,  309 
treatment,  309 
conjunctivitis  after,  298 
danger-signs,  296 
distention  of  stomach  and  intestines 

after,  297 
first  stage,  294 
fourth  stage,  296 
having  stomach  empty,  299 
helpful  measures  in,  298 
indications,  299 

injection  of  atropine  sulphate  in,  299 
intravenous,  307 
kidneys  after,  298 
nausea  after,  297 
pain  in  back  after,  297 
phagocytic   activity   of   leukocytes 

after,  305 
postoperative  gastric  or  intestinal 

paralysis  after,  298 
preliminary  administration  of  seda- 
tive drugs,  298 
anesthetization  with  chloroform, 

298 
with    nitrous    oxide    or    ethyl 

chloride,  298 
feeding  with  carbohydrates  and 

water,  299 

preventive  measures  in,  298 
reassuring  patient,  299 
recovery  from,  297 
respiratory  troubles  after,  298 
second  stage,  295 
sore  tongue  after,  298 
third  stage,  295 
thirst  after,  297 
untoward  sequels,  298 
vomiting  after,  297 
warming  vapor,  299 
compound  spirit,  dose,  284 
dose,  284 
elimination,  287 


INDEX 


627 


Ether  habit,  288 
inhalations  in   strychnine  poisoning, 

.279 

nitrous,  spirit  of,  240 

petroleum,  576 

pharmacologic  action,  285-288 

preparations  and  doses,  284 

rash,  288 

spirit  of,  dose,  284 

therapeutics,  288 
Ethyl  alcohol,  316 

bromide  anesthesia,  313 

chloride,  312 
anesthesia,  312 
preliminary  anesthetization  with,  in 

ether  anesthesia,  298 
spray,  425 

ester  of  para-amido-benzoic  acid,  424 

oxide,  284 

Ethylated  compounds,  364 
Ethylhydrocupreine,  479 

hydrochloride,  471 

in  pneumonia,  479 

in  ulcus  cornea;  serpens,  479 

poisoning  from,  479 
Ethyl-morphine  hydrochloride,  391 
Eucaine,  423 
Eucalyptol,  106,  504 
Eugenol,  106,  504 
Euonymus,  136 

dose,  137 
Euquinine,  471 
Europhen,  499 
Evacuating  enema,  144 
Exalgine,  462 
Excipient,  586 

Exercise  as  cathartic  measure,  122 
Exophthalmic  goiter,  atropine  in,  408 
pituitary  extract  in,  210 
quinine  in,  476 
Expectant  treatment,  61 
Expectorants,  563 
Experimentation,  animal,  58 
Extract,  definition,  41 
Extraction,  37 
Extractive,  38 
Extractum,  definition,  41 

malti,  72 
Eye,  diseases  of,  atropine  in,  407 

disinfectants,  516 


FALSE  anesthesia,  297 
Fat  allies,  32 

sweating  and,  446 
Fats,  29 
Fatty  degeneration  of  heart,  digitalis  in, 

192 

Feces,    impacted,    cathartic    enema    to 
soften,  144 

mechanical  agents  to  give  bulk  and 
soft  consistency  to,  124 


Feces,  mechanical  agents  to  give  bulk 
and  soft  consistency  to, 
agar,  125 
agar-agar,  125 
liquid  petrolatum,  125 
phenolphthalein-agar,  125 
psyllium  seeds,  125 
regulin,  125 
sulphur,  124 
lotum,  125 
praecipitatum,  125 
whole  flaxseed,  125 
Fecundity,  alcohol  and,  352 
Feet,  sweating  of,  aluminium  chloride  in, 

536. 

salicylic  acid  in,  483 
Ferments,  27 

digestive,  81 
Ferratin,  538 
Ferri  hydroxidum  cum  magnesii  oxido, 

537 

Ferric  acetate,  538 
citrate,  538 
hydroxide,  537 
salts,  inorganic,  537 
tartrate,  538 

Ferrous  salts,  inorganic,  537 
sulphate,  493 

as  disinfectant,  536 
Ferruginous  waters,  147 
Ferrum,  536 

reductum,  537 
Fever,  aconite  in,  236 
alcohol  in,  354 
camphor  in,  217 
iodide,  558 
Fibrillation,  auricular,  digitalis  in,  190, 

194 

from  digitalis,  1-70 
ventricular,  from  digitalis,  171 
Fibrolysin,  So 

therapeutics,  80 
Field  mushroom,  443 
Filicic  acid,  amorphus,  for  tape-worms, 

119 

Filtration,  228 
Fischer's  solution,  96 

in  nephritis,  96 
Fixed  oils,  29 

as  cathartics,  127 
Flatulence,  chloroform  in,  292 

wood-charcoal  in,  no 
Flavors  for  prescription,  585 
Flaxseed,    whole,    to    increase    bulk    of 

feces,  125 

Flowers  of  sulphur  as  laxative,  125 
Fluidextract,  definition,  40 
Fluidextractum,  definition,  40 
Flutter,  auricular,  digitalis  in,  189 

from  digitalis,  170 
Fly  agaric,  442,  443 
Spanish,  77 


628 


INDEX 


Fly-blister,  77 

Food  as  cathartic  measure,  123 

iron,  538 

preservatives,  500,  515 

value  of  alcohol,  331-336 
Foot-bath,  mustard,  77 
Formaldehyde,  510 

poisoning  from,  511 

therapeutics,  511 
Formaldehyde- tannin,  115 
Formalin,  510 
Formic  acid,  89 

in  rheumatism,  89 
Formin,  512 

Formulary,  National,  46 
Fortified  wines,  318 
Fossy  jaw,  553 
Fowler's  solution,  541 
Foxglove,  157 
Fractures,  delayed  union,  thyroid  gland 

in,  562 

Frangula,  133 
Fraxinus  ornus,  28 
French  brandy,  319 
Fried's  rule  for  dosage,  49 
Fruit  acids,  90 

Fruits  as  cathartic  measure,  124 
Fullers'  earth,  no 
Functional  albuminuria,  iron  in,  540 
Fungi,  poisonous,  443 
Fungus,  death's-head,  442,  443 
Furfurol,  429,  430 


GAMBIR,  compound  tincture  of,  114 
Gamboge,  dose,  137 
Gangrene  from  phenol,  506 

in  ergotism,  571 
Ganja,  392 
Gas,  expulsion  of,  enema  for,  144 

illuminating-,  poisoning  from,  574 

oxygen,  578 

Gas-poisoning,  oxygen  in,  580 
Gasoline,  576 

poisoning,  576 
Gastric  irritation,  bismuth  in,  532 

juice,  appetite,  107,  324 
psychic,  107,  324 

paralysis,   postoperative,   after   ether 
anesthesia,  298 

ulcer,  scarlet  red  in,  80 
Gastritis,  chronic,  silver  nitrate  in,  533 
Gauze,  balsam,  501 
Gelatin,  70 

glycerinated,  71 

in  aneurysm,  71 

in  hemorrhage,  71 

in  shock,  71 
Gelatinum,  70 
Gelatose,  silver,  534 
Gelsemium,  428 

fluidextract,  428 


Gelsemium,  tincture,  428 

General  protoplasm  poisons,  56 

Gentian,  compound  tincture  of,  109 

Germicides,  488 

Gin, 319 

Glacial  acetic  acid,  89 

Gland,  suprarenal,  dried,  dose  of,  197 

thyroid,  560 
Glassfuls,  585 
Glauber's  salt,  dose,  138 
Glaucoma,  pilocarpine  hydrochloride  in, 

442 
Glomerulus  of  kidney,  functions,  451, 

452 
Glonoin,  239 

spirit  of,  240 
Glucose,  24-26,  28,  69 

as  diuretic,  70 

as  food,  70 

as  prophylactic  against  shock,  70 

in  delayed  chloroform  poisoning,  303 

therapeutics,  70 
Glucosides,  24 
Glucosum,  28,  69 
Gluside,  68 
Glutol  capsules,  510 
Glycerin,  30,  31 

action  and  uses,  31 

and  rose-water,  31 

as  cathartic,  127 

in  diabetes,  31 

suppositories,  31 
Glycerinated  gelatin,  71 
Glycerinum,  31,  127 
Glycerite,  definition,  41 

of  boroglycerin,  501 
Glycerites,  31 
Glyceritum,  definition,  41 
Glycerophosphates,  554 
Glyceryl,  29 

trinitrate,  239 
Glyco-heroine,  391 
Glycosides,  24 
Glycyrrhizin,  20 
Goiter,  colloid,  iodides  in,  559 
thyroid  gland  in,  562 

exophthalmic,  atropine  in,  408 
pituitary  extract  in,  210 
quinine  in,  476 

Gold  as  antiseptic  and  disinfectant,  500 
Goldenseal,  572 
Gonorrheal  ophthalmia,  Cr6d6's  method 

of  prophylaxis  against,  533 
Goulard's  extract,  525 
Gout,  alcohol  in,  343 

cimicifuga  in,  488 

colchicum  in,  487 

lithium  in,  92 

phenyl-cinchoninic  acid  in,  487,  488 

salicylic  acid  in,  484 
Grain-alcohol,  316 
Granatum  for  tape- worms,  119 


INDEX 


629 


Granatum,  poisoning  from,  119 
Granular  effervescent  salt,  definition,  42 
Granulated  opium,  373 
Green  soap,  31 
tincture  of,  31 

tea,  265 

Griping  from  cathartics,  121 
Guaiacol,  503 

carbonate,  503 
Guanin,  252 
Guarana,  253 
Guaza,  392 
Gum  arabic,  29 

British,  29 

cherry-,  29 

resin,  36,  40 
Gums,  27,  28 

lead  line  on,  528 
Gwathmey's  oil-ether  colonic  method  of 

anesthesia,  306 
Gymnemic  acid,  109 


HABIT,  chloroform,  292 
cocaine,  420 

treatment,  420 
coffee,  266 
ether,  288 

formation  as  cathartic  measure,  122 
hasheesh,  392 
heroine,  391 
kola,  266 
morphine,  384 
paraldehyd,  367 
tea,  266 
tobacco,  432 

Habits,  previous,  dose  and,  50 
Hall's  antidote  in  mercury  poisoning,  524 
Halogens,  free,  494 

compounds,  494 
Hands,  obstetrician's,  disinfectants  for, 

Si6 

surgeon's,  disinfectants  for,  516 
sweating  of,  aluminium  chloride  in,  536 

salicylic  acid  in,  483 
Hard  soap,  31 
Harrington's  solution,  519 
Hasheesh  habit,  392 
Hashish,  392 
Hay-fever,  calcium  in,  100 

epinephrine  in,  205 
Headache  from  smoking,  435 

quinine  in,  477 
Head's  areas,  74 

Heart,  action  of,  influences  affecting,  150 
remedies  affecting,  directly,  150 

indirectly,  150 

blood  in,  output  of,  influences  affect- 
ing, 149 

blood-supply,  154 
compensation,  156 
failure  of,  156,  157 


Heart  compensation,  failure  of,  digitalis 
in,  194 

threatened  failure,  157 
conditions  of,  influence,  on  usefulness 

of  digitalis,  192 
connective-tissue    changes    in,    from 

epinephrine,  201 
contractility,  152 

action  of  digitalis  on,  167 
depressants,  231 
dilatation  of,  156 

digitalis  in,  192 
failure,  oxygen  in,  580 
increased  force,  from  epinephrine,  200 
irritability  of,  from  digitalis,  168 
irritable,  of  soldiers,  435 
massage  of,  in  shock  and  collapse,  251 
muscle,  action  of  digitalis  on  circula- 
tion through,  1 66 
muscular    inability,    associated    with 

valvular  lesion,  192 
nutrition  of,  action  of  digitalis  on,  177 
optimum  rate,  152 

overexcitability  of,  from  digitalis,  169 
overirritability  of,  from  digitalis,  169 
premature   contractions;   digitalis  in, 

189 

rate,  152 
recuperative  power,  action  of  digitalis 

on,  177 

resistance,  151 
rest  force,  157 
rhythm  of,  coupled,  from  digitalis,  176 

influences  affecting,  152 

nodal,  from  digitalis,  170 

normal.  165 
digitalis  in,  191 

reversed,  from  digitalis,  171 
slowing  of,  from  digitalis,  165 

from  epinephrine,  200 
tobacco,  435 
tonicity  of,  action  of  digitalis  on,  166, 

167 

working  force,  157 
Heart-beats,  premature,  from  digitalis, 

169 
Heart-block,    complete,    from   digitalis, 

172 

digitalis  in,  189 
from  digitalis,  172 
incipient,  from  digitalis,  172 
partial,  from  digitalis,  172 
Heat,  75 

as  disinfectant,  492 
body,  methods  of  raising,  /\/\<\ 
Heat-regulating  centers,  463 

action  of  digitalis  on,  183 
Heavy  liquid  petrolatum,  33 
metals,  517 

oxide  of  magnesium,  96 
wine,  318 
Hedonal,  366 


INDEX 


Hellebore,  American,  236 
Helleboreln,  muscular  effects,  184 
Hemlock,  poison,  427 
Hemophilia,  transfusion  of  blood  in,  227 
Hemophysis,  sodium  chloride  as  prophy- 
lactic against,  94 
Hemorrhage,  calcium  in,  100 

epinephrine  in,  205 

gelatin  in,  71 

local,  epinephrine  to  prevent,  205 

mechanical  measures  in,  225 

nasal,  antipyrine  in,  469 
counterirritants  for,  78 

postpartum,  diluted  acetic  acid  in,  89 
epinephrine  in,  205 
ergot  to  prevent,  571 

saline  infusion  in,  230 

transfusion  of  blood  in,  226 
Hemorrhoids,  quinine  in,  477 
Henbane,  394 
Heredity,  alcohol  and,  352 
Heroine,  390 

glyco-,  391 

habit,  391 
Hexamethylenamine,  24,  512 

administration,  514 

therapeutics,  514 

untoward  effects,  513 
Hexamethylenamine-tannin,  115 
Highball,  320 
Hirudin,  247,  248 
Hirudo,  247 
Hodgkin's  disease,  sodium  cacodylate  in, 

542 

Hoffmann's  anodyne,  dose,  284 
in  angina  pectoris,  288 
in  dyspnea,  288 
in  hysteria,  288 
in  spasm,  288 
therapeutics,  288 
Hog-back  kidney,  351 
Holocaine,  424 
Homatropine,  23 

hydrobromide,  411 
Honey,  definition,  41 
Hooker  and  Satterlee's  method  of  blood 

transfusion,  226 
Hookworms,  treatment,  117 
Hops,  393 
Hormonal,  85 

in  chronic  constipation,  85 

in  tympanites,  85 
Horn  silver,  533 
Horrors,  348 
Hot-air  bath,  445 
Hot-pack,  444 
Humulus,  393 

lupulus,  393 
Hydragogue,  122 
Hydra  rgyri    chloridum    corrosivum    as 

disinfectant,  518 
mite,  129 


Hydrargyrum  cum  creta,  131 
Hydrastine,  572 

dose,  572 

elimination,  573 

hydrochloride,  dose,  572 
Hydrastininae  hydrochloridum,  573 
Hydrastinine,  24 

hydrochloride,  573 
therapeutics,  574 
Hydrastis,  114,  572 

canadensis,  572 

constituents,  572 

dose,  572 

elimination,  573 

fluidextract,  dose,  572 

glycerite,  dose,  572 

pharmacologic  action,  572,  573 

preparations,  572 

therapeutics,  573 

tincture,  dose,  572 
Kydrated  chloral,  358 
Hydremic  plethora,  454 
Hydriodic  acid,  diluted,  555 
Hydrochloric  acid,  therapeutics,  87 
Hydrocyanic  acid,  426 
diluted,  426 
preparations,  426 
therapeutics,  427 
Hydrotherapeutic  measures,  18 
Hygienic  measures,  17 
Hymenolepis  nana,  116 

remedies  for,  119 
Hyoscine,  395,  409 

as  anaphrodisiac,  409 

as  general  anesthetic,  409 

as  mydriatic  and  cycloplegic,  409 

as  narcotic,  409 

hydrobromide,  396 

in  delirium  tremens,  409 

in  insomnia,  409 

therapeutics,  409 
Hyoscyamine,  395,  408 

hydrobromide,  396 

sulphate,  396 
Hyoscyamus,  394,  395 

dose,  395 

niger,  394 

therapeutics,  408 

tincture,  396 

Hyperchlorhydria,  silver  nitrate  in,  533 
Hyperisotonic  solutions,  228 
Hyperthyroidism,  atropine  in,  408 

iodides  in,  559 

pancreatin  in,  83 

pituitary  extract  in,  210 
Hypertonic  solutions,  228 
Hypcrtrophied  tissue,  trichloracetic  acid 

for,  89 

Hypnotic  measures,  357,  358 
Hypnotics,  356 

ethylated,  364 

which  do  not  abolish  pain,  358 


INDEX 


631 


Hypnotics  which  may  be  used  to  abolish 

pain,  367 

Hypochlorites,  494 
Hypodermatic  administration,  53 

advantages,  54 

disadvantages,  54 
Hypodermatoclysis,  administration  by, 

55 

Hypodermic  administration  of  salicylic 
acid,  484 

injection  of  epinephrine,  205 

tablets,  53,  587 

Hypodermoclysis,  saline  infusion  by,  230 
Hypoisotonic  solutions,  228 
Hypophosphites,    compound   syrup   of, 

554 
dose,  269 

of  phosphorus,  554 
Hypophysis,  desiccated,  207 

sicca,  207 

Hypothyroidism,  thyroid  gland  in,  562 
Hypotonic  solutions,  228 
Hypoxanthine,  252 

Hysteria,  Hoffmann's  anodyne  in,  288 
Hysteric  conditions,  camphor  in,  217 


ICHTHYOL,  509 

as  intestinal  disinfectant,  509 
Idiosyncrasy,  dose  and,  50 
Ilex  cassine,  253 

Illuminating-gas,  poisoning  from,  574 
Immunity,  effect  of  anesthesia  on,  305 

quinine,  474 
Imperial  drink,  88 
Incompatibility,  58,  603 

chemic,  603 

depending  on  change  of  solvent,  603 
Incompatibles,  alkaloids,  22 
Indian  tobacco,  428 
Indication,  definition,  63 
Inebriety,  345 
Inertia,  uterine,  pituitary  extract  in,  210 

quinine  in,  477 
Infantile  paralysis,  epinephrine  in,  205 

wasting,  thyroid  gland  in,  562 
Infantilism,  pancreatic,  pancreatin  in,  82 

pituitary,  anterior  lobe  extract  in,  211 
Infections,  effect  of  anesthesia  on,  305 
Infectious    conditions,     transfusion    of 
blood  in,  227 

diseases,  digitalis  in,  195 
Infiltration  anesthesia,  Schleich's,  425 
Inflammation,  counterirritants  for,  78 
Influenza,  quinine  in,  477 
Infusion,  definition,  40 

intravenous,  55 

of  wild  cherry,  426 
Infusum,  definition,  40 
Ingluvin,  85 

in  nausea  and  vomiting  of  pregnancy, 
85 


Inhalation,  administration  through  lungs 

by,  55 

Inorganic  acids,  86 
action,  86 

poisoning  from,  treatment,  8; 
therapeutics,  87 
toxicology,  86 
Insomnia,  alcohol  in,  354 

hyoscine  in,  409 
Instruments,  surgical,  disinfectants  for, 

5i5 
Insufflation,  intratracheal,  anesthesia  by, 

3°7 
pharyngeal,  anesthesia  by,  309 

Intestinal  disinfectants,  517 
infections,  purified  animal  charcoal  in, 

no 

irritation,  bismuth  in,  532 
paralysis,  pituitary  extract  in,  210 
peristalsis,  morphine  in,  387 
postoperative,  after  ether  anesthesia, 

298 
worms,  anthelmintics  for,  115 

Intestines,    distention    of,    after    ether 

anesthesia,  297 
effect  of  calcium  in,  100 
small,  as  factor  in  defecation,  120 

Intoxicants,  316 

Intracutaneous  administration,  54 

Intramuscular  administration,  53,  54 
injection  of  epinephrine,  effects,  199 

Intratracheal  insufflation,  anesthesia  by, 

307 

Intravenous  administration  of  epineph- 
rine, 206 
dangers,  206 
of  ouabain,  196 
of  salicylic  acid,  484 
of  strophanthin,  196 
anesthesia,  307 
Bier's,  425 
paraldehyd  for,  307 
with  chloroform,  307 
with  cocaine,  422 
with  ether,  307 
infusion,  55 

of  salt  solution,  227 
injection,  55 

of  epinephrine,  effects,  199 
local  anesthesia,  425 
medication,  55 

Inunction,  administration  by,  55 
Invertase,  27 
lodalbin,  555 
Iodide  fever,  558 
Iodides,  555 
absorption,  556 
administration,  559 
and  alkaloids,  incompatibility,  22 
contraindications,  559 
excretion,  556 
in  actinomycosis,  558 


632 


INDEX 


Iodides  in  colloid  goiter,  559 

in  hyperthyroidism,  559 

in  syphilis,  558 

theory  of  action,  557 

in  tuberculosis,  theory  of  action,  557 

pharmacologic  action,  555-557 

preparations  and  doses,  555 

therapeutics,  558 

untoward  actions,  557 
Iodine,  498,  555 

absorption,  556 

and  alkaloids,  incompatibility,  22 

Churchill's  tincture,  499 

compound  solution,  555 

compounds,  antiseptic,  499 

content  of  thyroid  gland,  556,  560 

excretion,  556 

pharmacologic  action,  555-557 

phenol  compounds,  504 

therapeutics,  558 

tincture  of,  498,  555 

untoward  actions,  557 

waters,  147 
lodipin,  555 
lodism,  chronic,  558 
lodival,  555 
lodocasein,  555 
lodoform,  499,  555 

emulsion,  499 

poisoning,  499 
lodol,  499 
lodum,  555 
Ipecac,  564 

and  opium,  powder  of,  dose,  373 

as  diaphoretic,  566 

as  emetic,  566 

as  expectorant,  566 

as  nauseant,  566 

dose,  564 

fluidextract,  dose,  564 

in  amebic  dysentery,  566 

poisoning,  565 

preparations  and  doses,  564 

syrup,  dose,  564 

therapeutics,  566 

toxicology,  565 
Ipecacuanha,  564 
Irish  whiskey,  319 
Iron,  536 

absorption,  538 

and  ammonium  citrate,  538 
tartrate,  538 

and  potassium  tartrate,  538 

and  quinine,  citrate  of,  538 

and  strychnine,  citrate  of,  538 

artificial  organic  compounds,  538 

as  antidote  in  arsenic  poisoning,  537, 
547 

as  antiseptic  and  disinfectant,  500 

as  astringent,  536 

as  disinfectant,  536 

as  hematinic,  537,  540 


Iron  carbonate,  537 

chloride,  537 

effect  on  blood,  539 

food,  538 

in  anemia,  540 

in  chlorosis,  540 

in  functional  albuminuria,  540 

iodide,  537 

masked,  538 

metallic,  537 

organic,  538 

phosphate,  537 

poisoning,  540 

reduced,  537 

salts  of  organic  acids,  538 

sulphate,  537 
dried,  537 

therapeutics,  540 

toxicology,  540 
Irritable  heart  of  soldiers,  435 
Irritant  drugs,  time  to  give,  56 
Irritants,  126 
Irritation,  57 
Isoamylamine,  567 
Iso-nitroso-antipyrine,  462 
Isophysostigmine,  436 
Isopilocarpine,  439 
Isopral,  366 

Isoquinoline  opium  alkaloids,  373 
Isotonic  solutions,  228 
Itching  of  vulva,  cocaine  in,  421 

epinephrine  in,  205 
Ivy-poisoning,  potassium  permanganate 

in,  54i 


JABORANDI,  439 

Jaborine,  438 

Jalap  powder,  compound,  dose,  137 

resin  of,  dose,  137 
Jarisch-Herxheimer  reaction,  551 
Jasmine,  yellow,  428 
Jaw,  fossy,  553 
Jervine,  236 

pseudo-,  237 
Jimson-weed,  394 
Juice,  definition,  40 
Juniper,  compound  spirit  of,  319 
Junket,  84 


KALA-AZAR,  antimony  in,  552 
Kamala  for  tape- worms,  119 

poisoning  from,  119 
Kaolin,  1 10 

in  cholera,  no 

in  diarrhea,  no 

in  diphtheria,  1 10 

in  dysentery,  no 
Keratin,  36 

for  coating  pills,  586 
Kerosene  oil,  33 


INDEX 


633 


Kidneys,  action  of  digitalis  on,  180 

after  ether  anesthesia,  298 

decapsulation  of,  in  mercury  poison- 
ing, 524 

functions  of,  450,  451 

glomerulus  of,  functions,  451,  452 

hog-back,  351 

tubules  of,  functions,  451,  452 
Knock-out  drops,  363 
Kola,  253 

habit,  266 

Kolliker's  schema  to  show  reflex  arc,  273 
Korsakoff 's  psychosis,  347 
Kroenig  and  Gauss  method  of  producing 

twilight  sleep,  410 


LABARRAQUE'S  solution,  494 

Labor,  pituitary  extract  in,  untoward 

effects,  211 
Lactalbumin,  84 
Lactarius  torminosus,  443 
Lactase,  27 
Lactic  acid,  89 

for  tuberculous  ulcers  of  throat,  89 
in  diabetes,  90 
Lactophenin,  463 

Lactophosphate  of  lime,  syrup  of,  97 
Lactuca  virosa,  393 
Lactucarium,  393 

lozenges  in  cough,  393 

syrup,  393 

tincture,  393 
Lager  beer,  317 

Lambert-Patterson    treatment   of   mer- 
cury poisoning,  523 
Lambert's  treatment  of  alcoholism,  349 

of  morphinism,  386 
Lanolin,  32 
Lard,  30 
Larkspur,  236 
Laryngitis,  ammonium  chloride  in,  224 

croupous,  calomel  in,  521 

tuberculous,  antipyrine  in,  469 
Larynx  disinfectants,  517 
Lassar's  paste,  483 
Latin  adjectives,  589 

adverbs,  590 

conjunctions,  591 

in  prescription  writing,  587 

nouns,  588 

prepositions,  590 

verbs,  590 
Laudanum,  373 
Laughing-gas,  310 

anesthesia,  310 
Laurocerasus,  426 

Lavender,  compound  tincture  of,  107 
Laxative  measures,  122 

pills,  compound,  dose,  269 
Laxatives,  sulphur  sublimatum,  125 
Lazy  man  prescription,  595 


Lead,  525 

acetate,  525 

and  opium  pills,  525 
wash,  373,  525 

colic,  526 

encephalopathy,  527 

line  on  gums,  528 

oleate,  525 

palsy,  527 

plaster,  525 

poisoning,  526 
diagnosis,  528 
treatment,  528 
wrist-drop  in,  527 

preparations,  525 

subacetate,  525 

sulphate,  525 

toxicology,  526 ' 
Lead' water,  525 
Lecithin,  32,  554 

in  anemia,  555 
Leech,  247 

artificial,  248 

Leishmaniosis,  antimony  in,  552 
Lemonade,  88 
Lemon-juice,  40 
Leprosy,  carminatives  in,  105 
Leptandra,  136 

dose,  137 

Leucorrhea,  cane-sugar  in,  69 
Leukemia,  benzol  in,  577,  578 

lymphoid,  benzol  in,  578 

myeloid,  benzol  in  578 

sodium  cacodylate  in,  542 
Leukocytes,   phagocytic  activity,  after 

chloroform  or  ether  anesthesia,  305 
Leukomains,  23 
Levant  wormseed,  116 
Levo-hyoscyamine,  395,  408 
Levulose,  28 

in  testing  functional  power  of  liver,  28 
Licorice,  20 

mixture,  compound,  563 

powder,  compound,  552 
Light  liquid  petrolatum,  33 

wine,  318 

Lily-of-the-valley,  160 
Lime,  chloride  of,  494 

chlorinated,  404 

lactophosphate  of,  syrup  of,  97 
Lime-water,  97 
Limonis  succus,  40 

Lindemann's  method  of  blood  transfu- 
sion, 226 

Line,  lead,  on  gums,  528 
Liniment,  ammonia,  218 

chloroform,  213 

definition,  41 

of  soft  soap,  31 

soap,  213 
Linimentum,  definition,  41 

saponis  mollis,  31 


634 


INDEX 


Linseed  oil,  30 
Lipoids,  32 
Liquefied  phenol,  505 
Liqueurs,  320 
Liquid  albolene,  33,  125 
extracts  of  malt,  317 
paraffin,  33,  125 
petrolatum,  33,  125 
heavy,  33 

in  rheumatoid  arthritis,  33 
light,  33 
prescriptions,  583 

measures,  584 
vaseline,  33,  125 
Liquids,  administration,  585 
alcoholic,  40 
aqueous,  39 
miscellaneous,  40 
percentage,  38 
chemic,  38 
pharmaceutic,  38 
strength  of,  38 
Liquor  acidi  arsenosi,  541 
ammonii  acetatis,  224 
antisepticus,  504 
arseni  et  hydrargyri  iodidi,  541 
calcis,  97 

cresolis  compositus,  503 
definition,  40 
ferri  chloridi,  537 

et  ammonii  acetatis,  224,  538 
subsulphatis,  537 
formaldehydi,  510 
hydrogenii  dioxidi,  492 
hypophysis,  207 
magnesii  citratis,  dose,  138 
plumbi  subacetatis,  525 

dilutus,  525 
potassii  arsenitis,  541 
sodii  boratis  compositus,  505 
chloridi  physiologicus,  227 
Liquors,  distilled,  318 

from    fermented    saccharine    fruit- 
juices,  319 

from  malt  liquors,  319 
medicinal  dose,  321 
malt,  316 
Lithia  waters,  147 
Lithium,  92 
carbonate,  92 
citrate,  101,  102 
in  gout,  92 
poisoning,  93 
Liver,  functional  power  of,  levulose  in 

testing,  28 

in  disposal  of  ammonia,  220 
sluggish,  calomel  in,  131 
Lobar    pneumonia,    ethylhydrocupreine 

in,  479 
Lobelia,  428 

fluidextract,  428 

in  spasmodic  asthma,  428 


Lobelia  tincture,  428 

Lobeline,  428 

Local  action,  direct,  52 

remote,  52 

Locke's  solution  for  saline  infusion,  227 
Loco  disease,  212 
Loco-weed,  212 

Locomotor  ataxia,  salvarsan  in,  550 
Losophan,  499 
Lotio  flava,  520 

nigra,  520 

plumbi  et  opii,  373 
Lotion,  definition,  41 

plumbi  et  opii,  525 
Lugol's  solution,  555 
Lumbar  puncture  in  delirium  tremens, 

349 

Luminal,  365 
Lunar  caustic,  533 

Lungs,  administration  through,  by  in- 
halation, 55 
edema  of,  acute  paroxysmal,  morphine 

in,  387 

oxygen  in, 580 
Lupulin,  393 

fluidextract  of,  393 
Lymphoid  leukemia,  benzol  in,  578 
Lysol,  503 


MADEIRA  wine,  318 
Mad- weed,  212 
Magendie's  solution,  374 
Magma  bismuthi,  531 
magnesiae,  96 

dose,  138 

Magnan's  sign  in  cocaine  poisoning,  419 
Magnesia,  milk  of,  96 

dose,  139 

Magnesii  carbonas,  96 
oxidum,  96 

ponderosum,  96 
Magnesium,  96 
carbonate,  96 

dose,  138 
citrate,  dose,  138 
heavy  oxide  of,  96 
hydroxide,  96 

dose,  138 
oxide,  96 

dose,  138 
peroxide,  96 
sulphate,  313 

as  anesthetic,  313 

intraspinal  method,  314 
intravenous  use,  314 
Meltzer's  theory,  314 
dose,  138 
in  arthritis,  315 
in  cellulitis,  315 
in  chorea,  315 
in  convulsions,  315 


INDEX 


Magnesium  sulphate  in  delirium   tre- 

mens,  315 

in  epididymitis,  315 
in  erysipelas,  315 
in  pain,  315 
in  sciatica,  315 
in  spasmophilia,  315 
in  tetanus,  314 
poisoning  by,  143 
Malakin,  463,  486 
Malaria,  antinomy  in,  552 
bichloride  of  mercury  in,  521 
quinine  in,  477 
Malates,  90 

Male-fern  for  tape- worms,  119 
Malic  acid,  90 
Malnutrition,  cod-liver  oil  in,  72 

transfusion  of  blood  in,  227 
Malt,  extract  of,  72,  85 
liquid  extracts,  317 
liquors,  316 
Maltase,  27 
Manganese,  540 
dioxide,  540 
poisoning,  541 
Manna,  28 
Mannite,  28 

Mannitol  hexanitrate,  effect,  242 
Maranta,  28 
Masked  iron,  538 
Mass,  definition,  41 
Massa,  definition,  41 
ferri  carbonatis,  537 
hydrargyri,  131 
Massage  as  cathartic  measure,  123 

of  heart  in  shock  and  collapse,  251 
Mate,  253 
Materia  medica,  18 
Maximum  dose,  47 
Measures  and  weights,  43 
apothecaries',  43 

exact  equivalents,  44 
metric,  43 
Mechanical  applications,  68 

measures,  18 
Medicine-droppers,  584 
Medinal,  365 
Mel,  definition,  41 
Melanosis,  arsenic,  548 
Meltzer's  plan  of  treatment  with  mag- 
nesium sulphate  in  tetanus,  315 
theory  of  anesthetic  action  of  mag- 
nesium sulphate,  314 
Menopause,    premature    anterior    lobe 

extract  of  pituitary  gland  in,  211 
Menorrhagia,  ergot  in,  572 

quinine  in,  477 
Menstruum,  37 
Menthol,  106 

Menthol-camphor,  213,  217 
Mercurial  ointment,  520 
as  antiseptic,  519 


Mercurial  stomatitis,  522 
Mercurialized  serum,  intraspinal  injec- 
tion, 521 

Mercurials,  cathartic,  129 
Mercuric  chloride  and  alkaloids,  incom- 
patibility, 22 
as  disinfectant,  500,  518 
in  venereal  sores,  519 
Mercurophen  as  antiseptic,  519 

as  disinfectant,  500 
Mercury,  518 

administration,  by  intramuscular  in- 
jection, 520 
by  inunction,  520 
by  mouth,  520 
intravenous  route,  521 
ammoniated,   ointment    of,   as    anti- 
septic, 519 

as  antiseptic  and  disinfectant,  500 
as  disinfectant,  518 
bichloride  of,  as  disinfectant,  518 
dose,  520 
in  malaria,  521 
biniodide,  dose,  520 
elimination,  521 
in  syphilis,  519 
nitrate  of,    ointment,  as    antiseptic, 

5i9 

oleate  of,  520 

pill,  131 

poisoning,  522 

protoiodide,  dose,  520 

subsulphate  in  croup,  521 

succinimide  in  tuberculosis,  521 

systemic  action,  521 

toxicology,  522 

with  chalk,  131 

dose,  520 
Mesotan,  486 
Metallic  astringents,  113 

iron,  537 

salts,  caustic,  78 

Metals  and   their  compounds  as  anti- 
septics and  disinfectants,  499 

heavy,  517 
Methyl  alcohol,  355 

blindness  from,  355,  356 
poisoning  from,  355 

salicylate,  106 
Methyl-acetanilid,  462 
Methylene-blue  as  antiseptic,  509 
Methyl-ouabaln,  160 
Methyl-oxymethyl  ester  of  salicylic  acid, 

486 

Methyloxypurins,  252 
Methyl  -  para  -  amido  -  meta  -  oxybenzoic 

ester,  424 

Methyl-propyl-carbinol-urethane,  366 
Methyl-thionine  chloride,  509 
Metric  prescriptions,  581 

system,  43 
Meyer-Overton  theory  of  narcosis,  282 


636 


INDEX 


Milk,  clotting  of,  by  rennet,  calcium  in, 

99 

of  bismuth,  531,532 
of  magnesia,  96 

dose,  138 

peptonizing,  pancreatin  for,  83 
secretion  of,  effect  of  pituitary  extract 

on, 209 

sugar  of,  28,  69 
Milk-punch,  320 

brandy, 320 

Mindererus,  spirit  of,  224 
Mineral  oil,  Russian,  125 
oils,  33 
waters,  146 

effervescing,  146 
non-effervescent,  146 
non-thermal,  146 
sparkling,  146 
still,  146 
thermal,  146 
Minimum  dose,  47 
Mistura  cretae,  97 
definition,  40 
pectoralis,  160 

as  expectorant,  564 
Mitral  insufficiency,  digitalis  in,  193 

stenosis,  digitalis  in,  194 
Mixture,  definition,  40 
Monkshood,  231 
Monobromated  camphor,  213 
Monobrom-valeryl-urea,  366 
Monoglycol  ester  of  salicylic  acid,  486 
Monohydrated  sodium  carbonate,  92 
Monsel's  solution,  537 
Moore  and  Roaf  theory  of  narcosis,  282 
Moreau's  loop,  saline  cathartics  and,  141 
Morning  tonic,  345 
Morphine,  374 
absorption,  376 

and  atropine  in  hypodermatic  use,  389 
as  preliminary  to  general  anesthesia, 

387 

contraindications  or  cautions,  387 
di-acetyl,  390 
dose,  374 
excretion,  381 
habit,  384 
hydrochloride,  374 
in  acute  paroxysmal  edema  of  lungs, 

387 

in  cough,  387 
in  diabetes,  387 
in  intestinal  peristalsis,  387 
in  pain,  379,  387 
in  vomiting,  387 
pharmacologic  action,  374 — 383 
poisoning,  383,  384 

chronic-,  384 

treatment,  383 
powder,  compound,  374 
sulphate,  374 


Morphine,  susceptibility,  382 

therapeutics,  386 

to  induce  sweating,  387 

tolerance,  382 

toxicology,  383 

untoward  effects,  382 
Morphine-stupor,  410 
Morphinism,  384 

Lambert's  treatment,  386 

Petty's  treatment,  386 

pigment  atrophy  in,  386 

Stokes'  treatment,  386 

treatment,  385 

Mountain-sickness,  oxygen   as  preven- 
tive, 579 
Mouth,  administration  by,  53 

disinfectants,  516 
Mucilage,  29 

definition,  40 
Mucilago,  40 
Mucous   membranes,   effect  of  sodium 

bicarbonate  on,  94 
Muriate  of  ammonia,  223 
Muscarine,  442 

poisoning,  442 
Muscle,  cardiac,  action  of  digitalis  on 

circulation  through,  166 
Muscles,  bronchial,  action  of  strychnine 

on,  276 

Muscular  inability  of  heart  associated 
with  valvular  lesion,  digitalis  in,  192 

bone,  action  of  strychnine  on,  274 
Mushroom,  field,  443 

poisoning,  442 

treatment,  443 
Musk,  394 

dose,  394 

tincture,  dose,  394 
Mustard,  77 

foot-bath,  77 

oil  of,  volatile,  26 

paste,  77 

Mutual  helpers,  57 
Mydriatic,  definition,  403 
Myeloid  leukemia,  benzol  in,  578 
Myocarditis,  digitalis  in,  192 
Myricyl  palmitate,  32 
Myrosin,  25-27 
Myrrh,  114 
Myxedema,  thyroid  gland  in,  562 


NAME  of  patient  on  prescription,  582 

Naphtha,  576 
wood,  355 

Naphthalin,  504 

Narcophin,  374 

Narcosis,  282 

alcohol,  stages  o.,  331 
Meyer-Overton  theory,  282 
Moore  and  Roaf  theory,  282 
theories,  282 


INDEX 


637 


Narcosis,  Verworn's  theory,  283 

Narcotic  poisoning,  strychnine  in,  280 

Narcotics,  282 

Narcotine,  373 

Nasal  hemorrhage,  antipyrine  in,  469 

Nataloin,  133 

National  Formulary,  46 

Pharmacopceial  Convention,  46 
Natural  emulsion,  40 
Nauheim  bath  as  circulatory  stimulant, 

157 

Nausea  after  ether  anesthesia,  297 
and  vomiting  of  pregnancy,  ingluvin 

in,  85 

treatment,  112 
bismuth  in,  532 
cerium  in,  532 

Necator  americana,  treatment,  117 
Neosalvarsan,  543,  549 

contraindications  and  cautions,  551 
in  cerebrospinal  syphilis,  550 
in  syphilis,  549 
therapeutics,  549 
untoward  effects,  550 
Nephritis,  acute,  diuresis  in,  460 
chronic,  diuresis  in,  460 

interstitial,  aconite  in  reducing  high 

arterial  pressure  in,  233 
diaphoresis  in,  448 
diuretics  in,  456 
Fischer's  solution  in,  96 
Nervous  affections,  bromides  in,  371 
diseases,  atropine  in,  407 
calcium  in,  100 
strychnine  in,  280 
instability,  camphor  in,  217 
irritability,  bromides  in,  371 
stimulants,  central,  252 

peripheral,  436 
system,  central,  remedies  acting  on, 

252 

which  depress,  282 
effect  of  digitalis  on,  183 
peripheral  drugs  affecting,  394 
Neuralgia,  quinine  in,  477 
trifacial,  aconite  in,  236 

butyl  chloral  hydrate  in,  363 
veratrum  in,  238 
trigeminal,  alcohol  in,  354 
Neuromuscular  junction,  receptive   sub- 
stance at,  153 
Neutral  principles,  24 
Nevi,  nitric  acid  for,  87 

trichloracetic  acid  for,  89 
Nicoll  and  Post's  bacteria  table,  490,  491 
Nicotiana  Rustica,  429 

tabacum,  429 
Nicotine,  429 

pharmacologic  action,  430,  431 
poisoning,  acute,  431 

treatment,  431 
Nightshade,  deadly,  394 


Night-sweats  of  tuberculosis,  sulphuric 

acid  in,  88 
Niter,  240 
as  preservative,  500 
sweet  spirit  of,  240 
Nitrates,  239 
Nitric  acid,  86 

dilute,  therapeutics,  88 
for  warts  or  nevi,  87 
therapeutics,  87 
Nitrites,  239 

administration,  245 
excretion,  244 

pharmacologic  action,  240-244 
poisoning  from,  244 
preparations  and  doses,  239 
therapeutics,  244 
toxicology,  244 
Nitrogen  monoxide,  310 

anesthesia,  310 

Nitrogenous  excretion,  relation  of  dia- 
phoresis to,  447    ' 
Nitroglycerin,  239 

effect,  242 

Nitrohydrochloric  acid,  86 
diluted,  86 

therapeutics,  88 
Nitrous  ether,  spirit  of,  240 
oxide,  310 

anesthesia,  310 

preliminary  anesthetization  with,  in 

ether  anesthesia,  298 
Nodal  rhythm  of  heart  from  digitalis,  1 70 
Node,  sinus,  action  of  digitalis  on  circula- 
tion through, 165 
Nomenclature  of  alkaloids,  21 

of  pharmaceutic  preparations,  30 
Nose,  diseases  of,  cocaine  in,  420 

disinfectants,  516 
Nose-bleed,  counterirritants  for,  78 

epinephrine  in,  205 
Nouns,  Latin,  588 
Novaspirin,  485 
Novocaine,  423 
Nutrients,  68 

Nutrition,  poor,  cod-liver  oil  in,  72 
Nutritive  enema,  144 
Nux  vomica,  268 
constituents,  268 
preparations  and  doses,  268 


OBESITY,  diaphoretics  to  lessen,  449 
thyroid  gland  in,  562 

Obstetrician's  hands,  disinfectants  for, 
Si6    . 

Obstetrics,  scopolamine-morphine  anes- 
thesia in,  410 

Obstipation,  atropine  in,  407 

Occupation,  dose  and,  50 

Official  preparations,  45 

Oil,  almond,  30 


638 


INDEX 


Oil,  camphorated,  213 
castor,  30,  127 

administration,  128 

therapeutics,  128 
cocoanut,  30 
cod-liver,  30,  71 

in  chronic  bronchitis,  72 

in  malnutrition,  72 

in  poor  nutrition,  72 

in  rickets,  72 

in  spasmophilia,  72 

in  tuberculosis,  72 

preparations  and  doses,  72 

therapeutics,  72 
cottonseed,  30 
croton,  30,  136 

dose,  137 
kerosene,  33 
linseed,  30 

of  bitter  almond,  25,  426 
of  cade,  35,  504 
of  chenopodium  for  hookworms,  117 

for  pin- worms,  118 

for  round-worms,  118 

for  tape-worms,  118 

for  whip-worms,  118 

poisoning  from,  118 
of  cinnamon,  504 
of  cloves,  504 
of  mustard,  volatile,  26 
of  tar,  35 

of  turpentine  for  tape- worms,  119 
olive,  30,  127 
peanut,  30 
Russian  mineral,  125 
Oil-ether  colonic  method  of  anesthesia, 

306 

Oils,  empyreumatic,  34,  35 
essential,  34 
fixed,  29 

as  cathartics,  127 
mineral,  33 
volatile,  34 

as  antiseptics,  504 

occurrence,  34 

Ointment,  blue,  as  antiseptic,  519 
citrine,  as  antiseptic,  519 
definition,  42 
dima/on,  80 
mercurial,  520 
of  ammoniated  mercury  as  antiseptic, 

SIQ 

of  nitrate  of  mercury  as  antiseptic,  519 

of  yellow  oxide  as  antiseptic,  519 

phenol,  505 

white  precipitate,  520 
as  antiseptic,  519 

zinc,  530 
Ointments,  32 
Oleate,  definition,  42 

of  mercury,  520 
Oleatum,  definition,  42 


Olein,  29,  30 
Oleoresin,  definition,  40 

of  aspidium  for  tape-worms,  119 
Oleoresina,  definition,  41 
Oleoresins,  36 
Oleum  cadinum,  35 

lini,  30 

morrhuae,  30,  71 

olivse,  127 

picis  liquidae,  35 

ricini,  30,  127 

theobromatis,  30 

tiglii,  30 

dose,  137 
Olive  oil,  30,  127 
Operative  measures,  18 
Ophthalmia,  gonorrheal,  Cred6's  method 

of  prophylaxis  against,  533 
Opii  pulvis,  373 
Opium,  372 

absorption,  376 

alkaloids,  373 
isoquinoline,  373 
phenanthrene,  373 

and  ipecac,  powder  of,  dose,  373 

camphorated  tincture,  dose,  373 

contraindications  or  cautions,  387 

deodorized,  373 
tincture,  dose,  373 

extract,  dose,  373 

granulated,  373 

granulatum,  373 

in  diabetes,  387 

in  intestinal  peristalsis,  387 

in  pain,  379,  387 

in  vomiting,  387 

pharmacologic  action,  374-383 

poisoning,  383 
chronic,  384 
pin-point  pupils  in,  380 

powdered,  372 

preparations  and  doses,  373 

therapeutics,  386 

tincture,  373 

Optimum  rate  of  heart,  152 
Optochin,  471 

Orange,  compound  spirit  of,  320 
Orexine  hydrochloride,  109 

tannate,  109 
Organic  acids,  88 

drugs,  constituents,  19 
active,  19,  20 
inert,  19 

Oriental  sore,  antimony  in,  552 
Orthoform,  424 

therapeutics,  424 
Osmosis,  228 
Osteomalacia,  phosphorus  in,  554 

thyroid  gland  in,  562 
Ouabaln,  161 

elimination  of,  183 

intravenous  use,  196 


INDEX 


639 


Overton-Meyer  theory  of  narcosis,  282 
Ovoferrin,  538 
Oxalic  acid,  90 

poisoning  from,  90 
Ox-gall,  dried,  127 

extract  of,  127 

fresh,  126 
Oxidases,  27 
Oxidizers,  492 
Oxygen,  578 

as  preventive   of  mountain-sickness, 

579 

gas,  578 

in  bronchial  asthma,  580 

in  carbon  monoxide  poisoning,  580 

in  collapse  in  anesthesia,  580 

in  cyanosis,  580 

in  edema  of  lungs,  580 

in  gas-poisoning,  580 

in  heart  failure,  580 

in  pneumonia,  580 

in  uremia,  580 

inhalation  of,  in  strychnine  poisoning, 
279 

pharmacologic  action,  578 

therapeutics,  579 
Oxygenium,  578 
Oxymethyl-hydrastinine,  574 
Oxyntin,  88 
Oxypurins,  252 

Oxyuris  vermicularis,  remedies  for,  116 
Oxyxanthine,  252 


PACK,  cold-,  461 

hot-,  444 
Pain,  aconite  in,  235 

analgesic  antipyretics  in,  470 

atropine  in,  403 

bromides  in,  371 

chloral  hydrate  in,  363 

chloroform  in,  292 

codeine  in,  388 

counterirritants  for,  78 

in  back  after  ether  anesthesia,  297 

magnesium  sulphate  in,  315 

morphine  in,  379,  387 

salicylic  acid  in,  484 
Pains,  referred,  73 
Painter's  colic,  526 
Palmitin,  29 
Palsy,  lead,  527 

Pancreatic    infantilism,   pancreatin    in, 
82 

juice,   effect   of  pituitary  extract  on 

flow  Of,  2IO 

Pancreatin,  82 

for  peptonizing  milk,  83 

in  chronic  pancreatitis,  82,  83 

in  hyperthyroidism,  83 

in  pancreatic  infantilism,  82 

Pancreatinum,  82 


Pancreatitis,  chronic,  pancreatin  in,  82, 

83 

Pantopon,  374 
Papain,  85 

Papaver  somniferum,  372 
Papaverine,  373,  389 

elimination,  389 

hydrochloride,  389 

in  cough, 390 

in  pyloric  spasm,  390 

in  spasm,  390 

in  ureteral  stone,  390 

in  vomiting,  390 

poisoning  from,  389 

sulphate,  389 

therapeutics,  390 

toxicity,  389 
Paper,  definition,  42 
Para  -  amido  -  benzoic-acid  -  propyl  ester, 

424 
Para  -  amino  -  benzoyl  -  diethyl  -  amino- 

ethanol  chloride,  423 
Para-diethoxyl-ethenyl-diphenyl-amidin 

chloride,  424 
Paraffin,  33 

liquid,  33,  125 
Paraffinum,  33 
Paraform,  510 
Paraformaldehyd,  510 
Paraguay  tea,  253 
Para-hydroxy-phenylethylamine,  567 

effect  on  circulation,  569 
Paraldehyd,  366 

for  intravenous  anesthesia,  307 

habit,  367 

in  strychnine  poisoning,  279 

poisoning  from,  367 
Paralysis,  57 

gastric    or    intestinal    postoperative, 
after  ether  anesthesia,  298 

infantile,  epinephrine  in,  205 

intestinal,  pituitary  extract  in,  210 

lead,  527 

respiratory,  collapse  and,  249 

strychnine  in,  280 

Sunday-morning,  345 
Para-sulphondi-chloramino-benzoicacid, 

495 

Paregoric,  dose,  373 
Paresis,  general,  salvarsan  in,  550 
Paris-green,  546 
Paroxysmal  tachycardia,  digitalis  in,  189 

from  digitalis,  170 
Paroxysms  of  acroparesthesia,  quinine  in, 

477 

Pasta  zinci,  483 
Paste,  Lassar's,  483 

mustard,  77 

Pasteurization,  489,  492 
Patterson-Lambert  treatment  of  mercury 

poisoning,  523 
Peanut  oil,  30 


640 


INDEX 


Pear  brandy,  319 

cider,  318 

Pelletierine  for  tape- worms,  119 
Pepo  for  tape- worms,  119 
Pepsin,  27,  81, 
Pepsinum,  81 

Peptonizing  milk,  pancreatin  for,  83 
Percentage  liquids,  38 
chemic,  38 
pharmaceutic,  38 
strength  of  liquids,  38 
Perhydrol,  96 
Periodic  drinkers,  346 
Peripheral    arteries,    contraction,    from 

digitalis,  178 
nervous  stimulants,  436 

system,  drugs  affecting,  394 
resistance,  influences  affecting,  149 
Peristalsis,  intestinal,  morphine  in,  387 
Pernicious  anemia,  cholesterol  in,  32 

sodium  cacodylate  in,  542 
Peroxide  of  hydrogen,  492 
Peruvian  bark,  470 
Petrolatum,  33 
album,  33 
liquid,  33,  125 
heavy,  33 

in  rheumatoid  arthritis,  33 
light,  33 
white,  33 
Petroleum  benzin,  33 

ether,  576 

Petty's  treatment  of  morphinism,  386 
Pharmaceutic  chemistry,  18 
elixirs,  320 
measures,  18 
percentage  liquid,  38 
preparations,  37 
compound,  39 
definitions  of  kinds  in  common  use, 

39 

nomenclature,  39 

simple,  39 
Pharmacist,  18 
Pharmacodynamics,  18 
Pharmacognocist,  18 
Pharmacognosy,  18 
Pharmacologic  action,  62  ,63-65 
Pharmacologist,  18 
Pharmacology,  18 
Pharmacopoeia,  45 
definition,  45 
United  States,  45 
Pharmacy,  18 
Pharyngeal  insufflation,  anesthesia  by, 

3°9 
Pharyngitis,  acute,  ammonium  chloride 

in,  224 

Phasic  arhythmia  from  digitalis,  166,  176 
Phen-acetamide,  462 
Phenacetin,  462 
Phenanthrene  opium  alkaloids,  373 


Phenol,  504 

as  anesthetic,  425 

as  antiseptic,  508 

compounds,  501 
iodine,  504 

excretion,  507 

for  infected  cavities,  79,  508 

gangrene  from,  506 

glycerite,  505 

in  tetanus,  509 

liquefactum,  504,  505 

liquefied,  505 

ointment,  505 

pharmacologic  action,  505-507 

poisoning  from,  507 
treatment,  508 

preparations,  505 

therapeutics,  508 

toxicology,  507 

Phenolphthalein  as  laxative,  134 
Phenolphthalein-agar  to  give  bulk  and 

soft  consistency  to  feces,  125 
Phenolsulphonates,  non-toxic,  508 
Phenyl  salicylate,  485 
Phenyl-cinchoninic  acid,  487 

in  gout,  487,  488 
Phenyl-dimethyl-pyrazolon,  462 
Phenyl-quinoline-carboxylic  acid,  487 
Phlebotomy,  245  , 
Phlorhizin,  26 
Phloridzin,  26 
Phlorizin,  26 

Phosphoric  acid,  dilute,  therapeutics,  88 
Phosphorous  acid,  553 
Phosphorus,  553 

hypophosphites  of,  554 

in  osteomalacia,  554 

in  rickets,  554 

poisoning,  acute,  553 
chronic,  553 

therapeutics,  554 

toxicology,  553 
Phthalem  test,  135 
Physical  measures,  18 
Physiologic  limit  of  drug,  48 
Physiology  of  circulation,  148 
Physostigma,  436 

constituents,  436 

dose,  436 

excretion,  438 

extract,  dose,  436 
.    pharmacologic  action,  436-438 

poisoning  from,  438 

preparations  and  doses,  436 

therapeutics,  438 

tincture,  dose,  436 

toxicology,  438 

venenosum,  436 
Physostigmine,  436 

as  cathartic,  438 

pharmacologic  action,  436-438 

salicylate  as  cathartic,  124 


INDEX 


641 


Physostigmine  salicylate,  dose,  436 
Pick-me-up,  345 
Picraconitine,  231 

Pigment  atrophy  in  morphinism,  386 
Pill,  blue,  131 
compound  cathartic,  131 
definition,  41 
mercury,  131 
Pills,  Blaud's,  537 
compound  cathartic,  133 

rhubarb,  133 
enteric,  36,  586 
of  aloes,  133 
of  lead  and  opium,  525 
Pilocarpidine,  439 
Pilocarpine,  439 
as  diaphoretic,  442 
elimination,  441 
hydrochloride,  dose,  439 

in  glaucoma,  442 
nitrate,  dose,  439 
pharmacologic  action,  439-441 
poisoning  from,  441 
treatment,  441 
therapeutics,  441 
toxicology,  441 
Pilocarpus,  439 
as  diaphoretic,  442 
constituents,  439 
dose,  439 
elimination,  441 
fluidextract,  dose,  439 
jaborandi,  439 
microphyllus,  439 
pharmacologic  action,  439-441 
poisoning  from,  441 
treatment,  441 
preparations  and  doses,  439 
therapeutics,  441 
toxicology,  441 
Pilula  antiperiodica,  471 

sine  aloe,  471 
definition,  41 
ferri  carbonatis,  537 
Pilulae  catharticae  compositae,  137 

vegetabiles,  137 

Pink-root  for  round- worms,  117 
Pin-point  pupils  in  opium  poisoning,  380 
Pin-worms,  quinine  in,  476 

remedies  for,  116 
Pinus  palustris,  35 
Piperazine,  488 
Pituitary  extract,  207 
as  cathartic,  124 

effect  of,  on  cerebrospinal  fluid,  210 
on  flow  of  pancreatic  juice,  210 

of  saliva,  210 
on  secretion  of  milk,  209 
from  anterior  lobe,  effects  and  uses, 

211 

in  asthma,  211 
in  dwarfism,  211 

41 


Pituitary  extract  from  anterior  lobe  in 
dystrophia  adiposo-geni- 
talis,  an 

in  pituitary  infantilism,  211 
in  premature  menopause,  211 
from  whole  gland,  211 
in  collapse,  251 
in  diabetes  insipidus,  210 
in  exophthalmic  goiter,  210 
in  hyperthyroidism,  210 
in  intestinal  paralysis,  210 
in  labor,  untoward  effects,  211 
in  shock,  210,  251 
in  tympanites,  210 
in  uterine  inertia,  210 
pharmacologic  action,  207-210 
therapeutics,  210 
toxicology,  210 
gland,  anterior  lobe,  211 

whole  gland,  211 
infantilism,  anterior  lobe  extract  in, 

211 

Placebo,  61 

Plant  acids  and  their  salts,  20 
Plants,  essences  of,  34 
Plaster,  definition,  42 

lead,  525 
Pleistopon,  374 
Plethora,  hydremic,  454 
Pleural  effusion,  calcium  chloride  in,  100 
Plumbum,  525 
Pluto  water,  148 

concentrated,  148 
Pneumatic  suit,  Crile's,  in  shock,  225, 

251 

Pneumonia,  camphor  in,  217 
digitalis  in,  166,  195 
ethylhydrocupreine  in,  479 
oxygen  in,  580  • 
quinine  in,  477 
strychnine  in,  280 
Podophyllum,  136 
dose,  137 
resin  of,  dose,  137 
Poison,  cumulative,  47 

hemlock,  427 
Poison-cup,  443 

Poisoning  from  acetyl-salicylic  acid,  485 
from  aconite,  235 

treatment,  235 
from  alcohol,  344 
after-effects,  345 
treatment,  345 
from  ammonia,  222 
treatment,  222 

from  analgesic  antipyretics,  468,  469 
from  antimony,  552 
from  antipyrine,  468,  469 
from  arsenic,  acute,  546 

iron  as  antidote,  537,  547 
treatment,  547 
chronic,  547 


642 


INDEX 


Poisoning  from  arsenic,  chronic,  treat- 
ment, 548 

cumulative,  547 
from  aspidium,  119 
from  aspirin,  485 
from  atropine,  405 

treatment,  406 
from  barium,  212 
from  belladonna,  405 

treatment,  406 
from  benzine,  576 
from  benzol,  577,  578 
from  bismuth,  531 
from  boric  acid,  501 
from  bromides,  acute,  370 

chronic,  370 

treatment,  371 
from  bromoform,  372 
from  caffeine,  261 

treatment,  261,  262 
from  calcium,  100 
from  camphor,  216 
from  cantharides,  77 
from  carbon  monoxide,  574 
acute,  575 
chronic,  575 
oxygen  in,  580 
transfusion  of  blood  in,  576 
treatment,  576 
from  carminatives,  104 
from  chloral  hydrate,  acute,  362 

chronic,  362 

from  chloroform,  delayed,  302 
from  cocaine,  419 

Magnan's  sign  in,  419 

treatment,  419 
from  colchicum,  487 
from  copper,  529 
from  cyanides,  426 

treatment,  427 
from  digitalis,  184 

cumulative,  186 

overwhelming  dose,  184 

single  large  dose  by  mouth,  185 

symptoms,  186 

treatment,  188 
from  drastics,  135 
from  early-bird  mixture,  119 
from  epinephrine,  204 
from  ergot,  571 

chronic,  571 

from  ethylhydrocupreine,  479 
from  formaldehyd,  511 
from  gas,  oxygen  in,  580 
from  gasoline,  576 
from  granatum,  IIQ 
from  illuminating-pas,  574 
from  inorganic  acids,  treatment,  87 
from  iodoform,  499 
from  ipecac,  565 
from  iron,  540 
from  kamala,  119 


Poisoning  from  lead,  526 

diagnosis,  528 

treatment,  528 

wrist-drop  in,  527 
from  lithium,  93 
from  magnesium  sulphate,  143 
from  manganese,  541 
from  mercury,  522 

acute,  522 

treatment,  523 

calcium  sulphide  in,  524 

chronic,  524 
treatment,  525 

decapsulation  of  kidneys  in,  524 

Hall's  antidote,  524 

Lambert-Patterson       treatment, 
523 

salivation  in,  522 

venesecetion  and  transfusion  in, 
524 

Wilms'  treatment,  524 
from  methyl  alcohol,  355 
from  morphine,  383,  384 

chronic,  384 

treatment,  383 
from  muscarine,  442 
from  mushroom,  442 

treatment,  443 
from  mustard,  77 
from  nicotine,  acute,  431 

treatment,  431 
from  nitrites,  244 
from  oil  of  chenopodium,  118 
from  opium,  383 

chronic,  384 

pin-point  pupils  in,  380 
from  oxalic  acid,  90 
from  papaverine,  389 
from  paraldehyd,  367 
from  phenol,  507 

treatment,  508 
from  phosphorus,  acute,  553 

chronic,  553 
from  physostigma,  438 
from  pilocarpus,  441 

treatment,  441 

from  potassium  chlorate,  113 
from  pyridine,  431 
from  quinine,  476 
from  ricin,  27 
from  salicylic  acid,  482 
from  saline  infusion,  231 
from  santonin,  116,  117 
from  scarlet  red,  80 
from  sodium  chloride,  93 
from  stramonium,  394 
from  strychnine,  277 

treatment,  278 
from  sulfonal,  364,  365 
from  thyroid  gland,  561 
from  tobacco,  431 

chronic.  435 


INDEX 


Poisoning  from  trional,  364,  365 
from  veratrum,  238 
from  veronal,  365 
from  zinc,  530 

ivy-,  potassium  permanganate  in,  541 
narcotic,  strychnine  in,  280 
Poisonous  fungi,  443 
Poisons,  protoplasm,  general,  56 
Poliomyelitis,  anterior,  epinephrine  in, 

205 

Polycythemia,  benzol  in,  578 
Polyporus  albus,  41 2 
Pomegranate  root  bark  for  tape-worms, 

119 

Port  wine,  318 
Porter,  317 

Post  and  Nicoll's  bacteria  table,  490, 491 
Postpartum  hemorrhage,  diluted  acetic 

acid  in,  89 
epinephrine  in,  205 
ergot  to  prevent,  571 
Potassa  sulphurata  in  acne,  124 
Potassium,  92 
acetate,  101 
alum,  535 
bicarbonate,  92 
bisulphate,  25,  26 
bitartrate,  101,  102 

dose,  138 
carbonate,  92 
chlorate,  113 

in  stomatitis,  113 
poisoning  from,  113 
citrate,  101 
dose,  138 

effervescing,  dose,  138 
cyanide,  426 
hypochlorite,  494 
iodide,  245,  555 
nitrate,  240 

as  preservative,  500 
in  bronchial  asthma,  240 
permanganate,  540 

as  antiseptic  and  deodorizer,  493 
sulphate,  dose,  138 
tartrate,  101 
dose,  138 
Poulsson's  experiment  with  strychnine, 

170 

Poultice,  definition,  42 
Poultices,  76 

clay,  76 
Powder,  definition,  41 

of  ipecac  and  opium,  dose,  373,  564 
Powdered  opium,  372 
Precipitated  carbonate  of  zinc,  530 
chalk,  97 
sulphur  in  acne,  124 

to  give  bulk  and  soft  consistency  to 

feces,  125 

Pregnancy,    nausea    and    vomiting    of, 
ingluvin  in,  85 


Pregnancy,   nausea    and    vomiting  of, 

treatment,  112 
Prepared  chalk,  97 
Prepositions,  Latin,  590 
Prescription,  581 

abbreviations,  597 
special,  599 

aromatics,  585 

colors,  586 

compound,  591 

dating,  582 

directions  for  compounding,  583 
for  label,  583 

figuring  quantities,  593 

flavors,  585 

form,  591 

lazy  man,  595 

liquid,  583 
measures,  584 

name  and  quantity  of  each  ingredient, 

583. 
of  patient,  582 

of  apothecaries'  system,  581 

of  metric  system,  581 

shot-gun,  595 

signature,  583 

simple,  591 

superscription,  583 

sweetening  agents,  585 

vehicle,  585 

writing,  581 

good  usage,  595 
Preservatives,  489,  515 

food.  500,  515 

for  anatomic  material,  515 

for  antitoxins,  515 

for  vaccines,  515 

pharmaceutic,  515 
Preventive  medicine,  17 
Proctitis,  silver  nitrate  in,  534 
Propaesin,  424 

Prostration,  transfusion  of  blood  in,  227 
Protargol,  534 
Protectives,  67 

as  antemetics,  112 
Protoplasm  poisons,  general,  56 
Protoveratrine,  236 

pharmacologic  action,  238 
Prunus  virginiana,  426 
Pseudo-jervine,  237 
Pseudoleukemia,  benzol  in,  578 
Psoriasis,  chrysarobin  in,  81 
Psychic  antiseptics,  504 

gastric  juice,  107,  324 
Psychosis,  KorsakofT's,  347 
Psychotherapeutic  measures,  18 
Psychotrine,  564 

Psyllium  seeds  to  give  bulk  to  feces,  125 
Ptomains,  23 
Ptomatropine,  23 

Pulmonary  arteries,  action  of  digitalis  on 
circulation  through,  180 


644 


INDEX 


Pulmonary  circulation,  155 

Pulse  in  anesthesia,  309 

Pulsus  alternans,  digitalis  in,  189 

from  digitalis,  176 
Pulvis  cretae  compositus,  97 

definition,  41 

jalapae  compositus,  137 
Pumpkin-seed  for  tape-worms,  119 
Puncture,  lumbar,  in  delirium  tremens, 

349 
Pupils,    pin-point,  in  opium  poisoning, 

380 
Pure  alkaloids,  21 

solubility  of,  21 
Purgative,  122 

waters,  147 

Purgatives,  subcutaneous,  137 
Purified  animal  charcoal,  109 
Purins,  252 

Pyloric  spasm,  papaverine  in,  390 
Pyorrhea  alveolaris,  emetine  in,  566 
Pyramidon,  462 
Pyridine,  429 

poisoning,  431 
Pyrogallol,  504 


QUASSIN,  26 

Quebrachine  as  expectorant,  563 

Quebracho  as  expectorant,  563 

Quercitannin,  29 

Quinidine,  470 

Quinine,  21,  470 

absorption,  473 

administration,  478 

amaurosis,  474 

amblyopia,  474 

and  urea  hydrochloride,  471 
as  anesthetic,  425 
as  local  anesthetic,  476 

as  disinfectant,  476 

as  postoperative  prophylactic,  478 

bisulphate,  21,  471 

as  local  anesthetic,  476 

chocolates,  478 

dihydrochloride,  471 

elimination,  474 

hydrobromide,  471 

hydrochloride,  471 

immunity,  474 

in  amebic  colitis,  476 
dysentery,  478 

in  bacterial  infections,  477 

in  blackwater  fever,  478 

in  cold,  477 

in  exophthalmic  goiter,  476 

in  headache,  477 

in  hemorrhoids,  477 

in  influenza,  477 

in  malaria,  477 

in  menorrhagia,  477 

in  neuralgia,  477 


Quinine  in  paroxysms  of  acroparesthesia, 

477 

in  pin-worms,  476 
in  pneumonia,  477 
in  septicemia,  477 
in  skin  diseases,  477 
in  tuberculosis,  477 
in  uterine  inertia,  477 
pharmacologic  action,  471-476 
poisoning  from,  476 
rash,  475 
salicylate,  471 
sulphate,  21,  471 
tannate,  471,  478 
therapeutics,  476 
toxicology,  476 
untoward  symptoms,  476 


RACE,  dose  and,  50 
Rachitis,  phosphorus  in,  554 
Rash,  ether,  288 

from  bromides,  369,  370 

quinine,  475 
Receptive  substance  at  neuromuscular 

junction,  153 

Rectal  administration  of  salicylic  acid, 
484 

anesthesia,  306 

injections,  143 

irrigations  of  saline  solution,  145 

suppositories,  42,  145 

treatment,  143 
Rectum,  administration  by,  55 

disinfectants,  517 
Recuperating  power  of  heart,  action  of 

digitalis  on,  177 
Red  wine,  318 
Reddening,  72 
Reduced  iron,  537 
Referred  pains,  73 
Reflex  emetics,  in 
Reflexes,  271,  272 

convulsive,  272 

from  strychnine,  272 

coordinated,  272 

simple,  272 

varieties,  272 
Regulin  to  give  bulk  and  soft  consistency 

tofeces,  125 

Remote  local  action,  52 
Rennet,  84 

clotting  of  milk  by,  calcium  in,  99 
Rennin,  84 
Repeated  doses,  47 
Resin,  gum,  40 

of  jalap,  dose,  137 

of  podophyllum,  dose,  137 

of  scammony,  dose,  137 
Resins,  36 

gum,  36 
Resistance  to  disease,  alcohol  and,  352 


INDEX 


645 


Resorcin,  503 
Resorcinol,  503 

Respiration,    artificial,    in    strychnine 
poisoning,  279 

Cheyne-Stokes,  377 
Respiratory  paralysis,  collapse  and,  249 

system,  effect  of  digitalis  on,  183 

tract,  disinfectants,  517 

troubles  after  ether  anesthesia,  298 
Retention  of  urine  from  digitalis,  181 

of  water,  digitalis  in,  182 
Rhamnus  frangula,  133 

purshinana,  133 
Rheum,  134 
Rheumatism,   chronic,   disaphoresis   in, 

.45° 
cimicifuga  in,  488 

formic  acid  in,  89 
salicylic  acid  in,  483 
sodium  bicarbonate  in,  96 
Rheumatoid  arthritis,  liquid  petrolatum 

in,  33 

thyroid  gland  in,  562 
Rhinitis  tablets,  213,  396 
Rhubarb,  134 

pills,  compound,  133 
Rhythm,     coupled,     of     heart,     from 

digitalis,  176 

nodal,  of  heart,  from  digitalis,  170 
of  heart,  influences  affecting,  152 
normal,  165 

digitalis  in,  191 
reversed,  from  digitalis,  171 
Ricin,  27 

poisoning,  27 
Ricinus  communis,  27 
Rickets,  cod-liver  oil  in,  72 
phosphorus  in,  554 
thyroid  gland  in,  562 
Ringer-Locke  solution  for  saline  infusion, 

_228 

Ringer's  solution  for  saline  infusion,  228 
Risiccol,  128 

Roaf  and  Moore  theory  of  narcosis,  282 
Rochelle  salts,  101 
Rose-water  and  glycerin,  31 
Round-worms,  remedies  for,  116 
Rubefacient,  72 
Rubijervine,  236 
Rum,  319 
Russian  bath,  444 
mineral  oil,  125 

SABADILLA,  237 
Sabadine,  237 
Sabadinine,  237 
Saccharin,  68 
Saccharum,  27,  69 

lactis,  28,  69 
Safrol,  107 
Sajodin,  555 


Sal  ammoniac,  223 

granulatus  effervescens,  definition,  42 
Salads  as  cathartic  measure,  123 

Salicin,  24,  25,  486 
Salicyl  alcohol,  25 
Salicylic  acid,  480 

absorption,  481 

administration,  484 

as  surgical  antiseptic,  483 

dose,  480 

excretion,  482 

hypodermatic  use,  484 

in  bromidrosis,  483 

in  chorea,  483 

in  corns,  483 

in  diabetes,  484 

in  gout,  484 

in  pain,  484 

in  rheumatism,  483 

in  skin  diseases,  483 

in  sweating  of  feet  and  hands,  483 

in  warts,  483 

intravenous  administration,  484 

pharmacologic  action,  480-482 

poisoning  from,  482 

preparations  and  doses,  480 

rectal  administration,  484 

therapeutics,  483 

toxicology,  482 
allies,  484 
jag,  483 

Salicylic-acetanilid,  486 
Salicyliden-para-phenetidin,  486 
Salicylism,  482 
Salicyl-para-phenetidin,  486 
Saligenin,  25 
Saline  cathartics,  137 

doses,  138 

in  constipation,  objections,  143 

Moreau's  loop  and,  141 

pharmacologic  action,  139-142 

preparations,  138 

therapeutics,  142 

time  to  give,  56 
infusion,  227 

by  enema,  230 

by  hypodermoclysis,  230 

colon  irrigations,  145 

continuous  drop  irrigation,  145 

contraindications,  231 

Dawson's  solution,  227 

effects,  228 

of  rate  of  flow,  230 

of  temperature  of  solution,  230 

on  respiration,  230 

when   volume  of  blood  has  not 

been  decreased,  228 
is  below  normal,  229 

in  cholera,  230 

in  collapse,  230 

in  ether  collapse,  309 

in  hemorrhage,  230 


646 


INDEX 


Saline  infusion  in  shock,  230 
in  strychnine  poisoning,  279 
in  toxemic  conditions,  230 
intravenous,  227 
Locke's  solution,  227 
normal,  227 
poisoning  by,  231 
rectal  irrigations,  145 
Ringer-Locke  solution,  228 
Ringer's  solution,  228 
therapeutics,  230 
toxicology,  231 
waters,  147 

alkaline,  147 
Saliphen,  486 
Salipyrine,  462 
Saliva,  effect  of  pituitary  extract  on  flow 

of,  210 

Salivation  in  mercury  poisoning,  522 
Salol,  485 

for  coating  pills,  586 
Salophen,  462,  486 
Salt,  Epsom,  as  anesthetic,  313 

dose,  138 

Glauber's  dose,  138 
granular  effervescent,  definition,  42 
retention,  relation  of,  edema  to,  93 
Salt-free  diet,  prolonged,  results  of,  93 
Saltpeter,  240 

as  preservative,  500 
Salts,  alkaloidal,  21 

differences  in   physiologic  actions, 

24 

solubility  of,  21 
bile,  126 

metallic,  caustic,  78 
of  tartar,  92 
Salvarsan,  542.  549 

contraindications  and  cautions,  551 
in  cerebrospinal  syphilis,  550 
in  general  paresis,  550 
in  locomotor  ataxia,  550 
in  non-syphilitic  cases,  552 
in  syphilis,  549 
therapeutics,  549 
untoward  effects,  550 
Salves,  32 

Santonica  for  round- worms,  116 
Santonin,  26,  116 

poisoning  from,  116,  117 
Santoninum,  116 
Sapo,  31,  127 

mollis,  31 
Satterlee  and  Hooker's  method  of  blood 

transfusion,  226 
Scammony,  resin  of,  dose,  137 
Scarlet  red,  79 

Schleich's  infiltration  anesthesia,  425 
Sciatica,  magnesium  sulphate  in,  315 
Scientific  therapeutics,  58 
Scilla,  160 
Scilkun,  1 60 


Scillitoxin,  160 
Scoparius,  428 
Scopolamine,  409 

hydrobromide,  396 
Scopolamine-morphine  anesthesia,  409 

as  preliminary  to  general  anesthesia, 

410 

Scopolamine-narcophin  anesthesia,  409 
Scotch  whiskey,  319 
Seasickness,  chloretone  in,  364 

treatment,  113 
Secretin,  85 
Secretion,  atropine  to  diminish,  406 

threshold  in  diuresis,  457 
Sedatives,  central,  as  antemetics,  112 

local,  as  antemetics,  112 
Seidlitz  powder,  138 
Selective  drugs,  56 
Semisolids,  41 
Senega  as  expectorant,  563 
Senna,  133, 134 

tea,  133 

Sepsis,  transfusion  of  blood  in,  227 
Septicemia,  quinine  in,  477 
Serum,  Beebe's,  562 

mercurialized,    intraspinal    injection, 
521 

salvarsanized,  in  cerebrospinal  syphilis, 
550 

sickness,  atropine  in,  408 

calcium  in,  100 
Sevum,  30 
Sex,  dose  and,  50 
Sexual  feebleness,  strychnine  in,  280 

hyperesthesia,  bromides  in,  371 
Shakes,  brass,  530 
Sheet,  drip-,  461 

Sherrington's  theory  of  action  of  strych- 
nine on  muscles,  273 
Sherry  wine,  318 
Shock,  248 

alcohol  in,  354 

anaphylactic,  epinephrine  to  check,  205 

camphor  in,  217 

carbon  dioxide  in,  252 

Crile's  anoci-association    as    prophy- 
lactic, 249,  250 
pneumatic  suit  in,  225,  251 

epinephrine  in,  206,  251 

gelatin  in,  71 

massage  of  heart  in,  251 

mechanical  measures  in,  251 

pituitary  extract  in,  210,  251 

saline  infusion  in,  230 

stimulants  in,  251 

symptoms,  250 

transfusion  of  blood  in,  226,  251 

treatment,  250 

prophylactic,  250 
Shot-gun  prescription,  595 
Sickness,  mountain-,  oxygen  as  prevent- 
ive, 579 


INDEX 


647 


Sickness,  serum,  atropine  in,  408 

calcium  in,  100 

Sign,  Magnan's,  in  cocaine  poisoning,  419 
Signature  of  prescription,  583 
Silver,  533 

as  antiseptic,  534 

and  disinfectant,  500 
colloidal,  534 
gelatose,  534 
horn,  533 
nitrate,  533 
as  prophylactic  against  gonorrheal 

ophthalmia,  533 
in  chronic  gastritis,  533 
in  colitis,  534 
in  hyperchlorhydria,  533 
in  proctitis,  534 
therapeutics,  533 
protein,  534 
untoward  effects,  535 
vitellin,  534 
Sinalbin,  26 
Sinapine  sulphate,  26 
Sinapis,  77 
nigra,  77 
Sinigrin,  25,  26 
Sinus  arhythmia,  digitalis  in,  189 

from  digitalis,  166 
node,  action  of  digitalis  on  circulation 

through, 165 

Sinuses,  chronic,  Beck's  treatment,  532 
Skin,  administration  by,  55 
diseases,  disinfectants  in,  516 
quinine  in,  477 
salicylic  acid  in,  483 
disinfectants,  516 
irritation,  production  of,  72 
Sleep,  356 
twilight,  410 
Verworn's  theory,  356 
Sluggish  liver,  calomel  in,  131 

ulcers,  burnt  alum  in,  536 
Smoking,  429,  432 

effects  of,  435 
Snake-bite,  potassium  permanganate  in, 

540 

Snakeroot,  black,  488 
Snuff,  429 
Soamin,  542 
Soap, 31 

as  cathartic,  127 
Castile,  30,  31,  127 
detergent,  31 
green,  31 

tincture  of,  31 
hard,  31 
liniment,  213 
soft,  31 

liniment  of,  31 
soluble,  31 
Socaloin,  133 
Soda,  baking,  92 


Sodii  arsenas  exsiccatus,  541 
bicarbonas,  94 
nitris,  239 
Sodium,  92,  93 
acetate,  101 
acetyl  arsanilate,  542 
aminophenyl  arsonate,  542 
arsanilate,  542 
.  arsenate,  541 
dried,  541 
solution  of,  541 
aurate  as  antiseptic  and  disinfectant, 

500 

benzoate,  501 
bicarbonate,  92,  94 
administration,  in  ether  anesthesia, 

299 
effect  of,  on  alimentary  tract,  94 

on  mucous  membranes,  94 
in  acidosis,  95 
in  diabetes,  95 
in  rheumatism,  96 
time  of  administration,  95 
bisulphite,  493 
borate  as  preservative,  500 
cacodylate,  542 
carbonate,  monohydrated,  92 
chloride,  93 
as  preservative,  500 
as  prophylactic  against  hemoptysis, 

94 

poisoning,  93 
citrate,  101,  102 

dose,  138 

dimethyl  arsenate,  542 
glycocholate,  126 
hydroxide,  30 
hyposulphite,  493 
iodide,  555 
nitrite,  239 
dose,  239 
effect,  242 
oxymercury    orthonitrophenolate    as 

antiseptic,  519 
perborate,  493 
phosphate,  dose,  138 

effervescing,  dose,  138 
salicylate,  dose,  480 
sulphate,  dose,  138 
sulphite,  493 
tartrate,  101 
dose,  138 
taurocholate,  126 
thiosulphate,  493 
Sodium-benzosulphinide,  68 
Sodium-saccharin,  68 
Sodium-salvarsan,  543 
Soft  soap,  31 

liniment  of,  31 

Soldiers,  irritable  heart  of,  435 
Solid  albolene,  33 
Solids,  41 


r 


648 


INDEX 


Solids,  administration,  586 

semi-,  41 
Solubility  of  alkaloidal  salts,  21 

of  alkaloids,  21 

of  atropine,  21 
sulphate,  21 

of  pure  alkaloids,  21 
Solution,  definition,  40 

of  aluminium  acetate,  536 

of  ammonium  acetate,  224 

of  arsenous  acid,  541 

of    epinephrine    hydrochloride,  dose, 
197 

of  iron  and  ammonium  acetate,  224 

of  sodium  arsenate,  541 

hypochlorite,  494 
Sore,  oriental,  antimony  in,  552 

tongue  after  ether  anesthesia,  298 
Sores,  venereal,  mercury  in,  519 
Spanish  fly,  77 
Sparkling  mineral  waters,  146 

wine,  318 
Sparteine  sulphate,  428 

in  spasmodic  asthma,  428 
Spasm,  Hoffmann's  anodyne  in,  288 

of  urethra,  cocaine  in,  421 

papaverine  in,  390 

pyloric,  papaverine  in,  390 
Spasmodic  asthma,  lobelia  in,  428 
sparteine  sulphate  in,  428 
stramonium  in,  408 
Spasmophilia,  cod-liver  oil  in,  72 

magnesium  sulphate  in,  315 
Specific  treatment,  60 
Spelter  chills,  530 
Spermaceti,  32 
Spices,  107 

Spigelia  for  round-worms,  117 
Spinal  anesthesia  in  strychnine  poisoning, 

.279 

with  cocaine,  414,  415,  421 
with  stovaine  and  strychnine,  415 
Spirit,  definition,  40 

of  bitter  almond,  426 

of  glonoin,  240 

of  hartshorn,  218 

of  mindererus,  224 

of  nitrous  ether,  240 
Spirits,  318 
Spiritus  ammoniac  aromaticus,  218 

definition,  40 

frumenti,  319 

glycerylis  nitratis,  240 

vini  gallici,  319 
Spirosal,  486 
Splint,  bowel,  375,  376 
Spoonfuls,  584 

Sporotrichosis,  copper  sulphate  in,  529 
Spotted  boy,  535 
Squibb's  diarrhea  mixture,  146,  213 

test  for  aconite,  232 
Squill,  1 60 


Squill,  compound  syrup  of,  552 
as  expectorant,  564 

fluidextract  of,  dose,  160 

syrup  of,  1 60 
compound,  160 

tincture  of,  dose,  160 
Staphisagria,  236 
Starch,  arrowroot,  28 

corn-,  28 

water,  28 
Starches,  27 
Stavesacre,  236 
Steady  drinkers,  346 
Stearin,  29 
Stearoptens,  35,  106 
Stenosis,  aortic,  digitalis  in,  194 

mitral,  digitalis  in,  194 
Sterilization,  489 
Still  mineral  waters,  146 
Stimulants,  central  nervous,  252 

circulatory,  157 

peripheral  nervous,  436 
Stimulation,  57 
Stokes'  expectorant,  160,  564 

treatment  of  morphinism,  386 
Stomach,  diseases  of,  cocaine  in,  421 

disinfectants,  517 

distention  of,  after  ether  anesthesia,. 
297 

ulcer  of,  orthoform  in,  424 

scarlet  red  in,  80 
Stomatitis,  mercurial,  522 

potassium  chlorate  in,  113 
Stout,  317 
Stovaine,  423 

and  strychnine,  spinal  anesthesia  with,. 

415  . 
Stramonium,  394,  395 

dose,  395 

in  spasmodic  asthma,  408 

ointment,  396 

tincture,  396 
Strong  wine,  318 
Stronger  ammonia  water,  218 
Strontium  salicylate,  dose,  480 
Strophanthin,  24,  160 

dose,  160 

elimination  of,  183,  184 

intravenous  use,  196 
Strophanthus,  160 

absorption,  from  alimentary  tract,  183; 

constituents,  160 

dose,  1 60 

hispidus,  1 60 

Kombe,  160 

preparations,  160 
and  doses,  160 
reliability  of,  162 

tincture  of,  dose,  160 
Strychnine,  268,  269 

absorption,  269 

action  on  reflexes,  280 


INDEX 


649 


Strychnine,  administration,  281 
as  tonic,  280 

Bernard's  experiment,  271 
caffeine  and,  comparison   of  action, 

275 

contraindications,  281 

convulsive  reflexes  from,  272 

excretion,  277 

in  cough,  276 

in  diminished  vision,  281 

in  narcotic  poisoning,  280 

in  nervous  diseases,  280 

in  paralysis,  280 

in  pneumonia,  280 

in  sexual  feebleness,  280 

nitrate,  269 
dose,  269 

pharmacologic  action,  269-277 

poisoning  from,  277 
treatment,  278 

poisonous  action,  275 

Poulsson's  experiment,  270 

preparations  and  doses,  268 

Sherrington's  theory,  273 

sulphate,  269 
dose,  269 

testing  clinically,  275 

therapeutics,  280 

tolerance,  277 

toxicology,  277 
Strychnos  nux  vomica,  268 
Stupe,  75 
Stupor,  282 

morphine-,  410 

of  alcoholics,  344 
Stypticin,  574 
Styptics,  115 

Subcutaneous  administration,  53 
superficial,  54 

injection  of  epinephrine,  effects,  199 

purgatives,  137 

Subinvolution  of  uterus,  ergot  in,  572 
Sublimed  sulphur  as  laxative,  125 
Succinyl  disalicylic  acid,  485 
Succus,  definition,  40 
Suet,  30 
Sugar,  69 

of  milk,  28,  69 

susceptibles,  68 
Sugars,  27,  28 
Suggestive  measures,  18 
Sulfonal,  364 

poisoning  from,  364,  365 
Sulphocarbolates,  non-toxic,  508 
Sulphonmethanum,  364 
Sulphonethylmethanum,  364 
Sulphur  dioxide,  493,  494 

flowers  of,  as  laxative,  1 25 

lotum  to  give  bulk  and  soft  consist- 
ency tofeces,  125 

prsecipitatum   to  give  bulk  and  soft 
consistency  to  feces,  125 


Sulphur,  precipitated,  in  acne,  124 

to  give  bulk  and  soft  consistency  to 
feces,  125 

sublimatum  as  laxative,  125 

sublimed,  as  laxative,  125 

to  give  bulk  and  soft  consistency  to 
feces,  124 

washed,  to  give  bulk  and  soft  consis- 
tency to  feces,  125 

waters,  147 

Sulphurated  waters,  146 
Sulphuric  acid,  action  of,  78 
aromatic,  86 

.    in  night-sweats  of  tuberculosis,  88 
Sulphurous  acid,  493 
Sun  cholera  drops,  213 

mixture,  146 

Sunday-morning  paralysis,  345 
Superheated  air,  450 
Superscription  of  prescription,  583 
Suppositoria  glycerini,  31 
Suppositorium,  definition,  42 
Suppository,  definition,  42 

glycerin,  31 

rectal,  42,  145 

urethral,  42 

vaginal,  42 

Suppression  of  urine  from  digitalis,  181 
Supracapsulin,  196 
Suprarenal  gland,  dried,  dose,  197 
Suprarenalin,  196 
Suprarenalum  siccum,  197 
Suprarenine,  23 

Surgeon's  hands,  disinfectants  for,  516 
Surgical  instruments,  disinfectants  for, 

515 

supplies,  disinfectants  for,  515 
Susceptibility,  dose  and,  50 
Sweat,  character  of,  in  diaphoresis,  447 
Sweating,  excessive,  agaricin  in,  412 

morphine  to  induce,  387 

of  feet  and  hands,  salicylic  acid  in,  483 

of  hands,  feet,  and  axillae,  aluminium 
chloride  in,  536 

profuse,  443 

rationale  of,  445 
Sweet  spirit  of  niter,  240 

wine,  318 
Sweetening  agents,  68 

for  prescription,  585 
Symptomatic  treatment,  60 
Synergists,  57 
Syphilis,  cerebrospinal,  neosalvarsan  in, 

55° 

salvarsan  in,  550 
iodides  in,  558 

theory  of  action,  557 
mercury  in,  519 
neosalvarsan  in,  549 
salvarsan  in,  549 
sodium  cacodylate  in,  542 
Syrup,  definition,  40 


INDEX 


Syrup  of  lactophosphate  of  lime,  97 
of  phosphates  of  iron,  quinine,  and 

strychnine,  537 
dose,  269 
of  squill,  1 60 

compound,  160 
of  tar,  35,  504 
of  wild  cherry,  426 
of  yerba  santa,  109 
Syrupus  calcii  lactophosphatis,  97 
definition,  40 
picis  liquidas,  35,  504 
Systemic  action  of  drugs,  52 

arteries,  action  of  digitalis  on  circula- 
tion through, 178 


TABACUM,  429 

Tabella  compressa,  definition,  41 

triturata,  definition,  41 
Tablet,  compressed,  definition,  41 

triturate,  definition,  41 

triturates,  587 
Tablets,  compressed,  587 

hypodermic,  53,  587 
Tachycardia,   paroxysmal,   digitalis   in, 

189 

from  digitalis,  170 
Tasnia  nana,  116 

saginata,  remedies  for,  119 
Taka-diastase,  85 
Tallow,  30 
Tannalbin,  115 
Tannate,  egg-albumin,  115 
Tannic  acid,  29,  114 

and  alkaloids,  incompatibility,  22 
astringents,  114 
of  coffee,  264 
of  tea,  265 
therapeutics,  115 
Tannigen,  115 
Tannin,  114 

formaldehyde-,  115 

hexamethylenamine-,  115 
Tannins,  29 
Tannoform,  115 
Tannopin,  115 
Tape-worms,  dwarf,  remedies  for,  119 

remedies  for,  119 
Tar,  504 

oil  of,  35 

syrup  of,  35,  504 
Tartar,  cream  of,  101,  102 
dose,  138 

emetic,  552 

salts  of,  92 
Tartaric  acid,  88,  90 
Taste  of  alkaloids,  22 
Tea,  253,  264,  265 

action,  265,  266 

Appalache,  253 

black,  265 


Tea,  green,  265 
habit,  266 
Paraguay,  253 
senna,  133 
tolerance,  266 
Temperature,  dose  and,  50 
Teniacides,  119 
Teniafuges,  119 
Terminal  disinfection,  515 
Terra  silicea  purificata,  1 1 1 
Test,  Squibb's,  for  aconite,  232 

urotropin,  512 
Tetanus,  Epsom  salt  in,  314 
magnesium  sulphate  in,  314 
phenol  in,  509 
calcium  in,  98,  100 
Tethelin,  211 
Tetra-iodo-pyrrhol,  499 
Theobroma  cacao,  267 
Theobromine,  252,  253,  263,  264 
diuretic  action,  456 
sodiosalicylate,  264 
Theocine,  264 

diuretic  action,  456 
Theophylline,  23,  252,  263,  264 

diuretic  action,  456 
Therapeutic  dose,  47 
Therapeutics,  62 
definition  of,  17 
empiric,  58 
scientific,  58 

Thermal  mineral  waters,  146 
Thiersch's  solution,  500 
Thiol,  509 

Thiosinamine,  26,  80 
Thirst  after  ether  anesthesia,  297 
Thornapple,  394 
Thread-worms,  remedies  for,  116 
Throat,  diseases  of,  cocaine  in,  421 
disinfectants,  516 

tuberculous  ulcers  of,  lactic  acid  in, 
Thymol  for  hookworms,  117 
in  trichinosis,  117 
iodide,  499,  504 
Thyreoglobulin,  560 
Thyreoidectin,  563 
Thyroid  gland,  560 

after  thyroidectomy,  562 

in  colloid  goiter,  562 

in  creatinism,  562 

in  delayed  union  of  fractures,  562 

in  hypothyroidism,  562 

in  infantile  wasting,  562 

in  myxedema,  562 

in  obesity,  562 

in  osteomalacia,  562 

in  rheumatoid  arthritis,  562 

in  rickets,  562 

iodine  content,  556,  560 

pharmacologic  action,  561 

poisoning  from,  561 

relation  to  adrenals,  561 


INDEX 


Thyroid  gland,  therapeutics,  562 
Thyroidectomy,  thryoid  gland  after,  562 
Thyroideum  siccum,  560 
Thyroidin,  560 

Tic,  cocaine  as  diagnostic  agent  in,  421 
Tinctura  antiperiodica,  471 
cardamomi  composita,  107 
cinchonae  composita,  109 

dose,  470 
definition,  40 
gentianas  composita,  109 
lavandulse  composita,  107 
moschi,  dose,  394 
Tincture,  definition,  40 

of  green  soap,  31 
Tobacco,  429 
amblyopia,  435 
effects  of  smoking,  435 
habit,  423 
heart,  435 
in  asthma,  430 
Indian,  428 
poisoning  from,  431 

chronic,  435 
therapeutics,  430 
tolerance,  431 
toxicology,  431 
Toleration,  dose  and,  50 
Toluene  parasulphochloramin,  498 

parasulphondichloramin,  498 
Toluol-azotoluol-azobetanaphthol,  79 
Tone-waves,  398 

Tongue,  sore,  after  ether  anesthesia,  298 
Tonic,  morning,  345 
Toothache,  chloral  hydrate  in,  362 

chloroform  in,  292 
Torpor,  282 
Toxalbumins,  26 
Toxemic  conditions,  saline  infusion  in, 

230 

Toxic  dose,  47 
Toxicology,  definition,  62 
Toxins,  26 
Toxitabella  hydrargyri  chloridi  corrosivi, 

Si8 

Tragacanth,  28,  29 
Transfusion  and  venesection  in  mercury 

poisoning,  524 
of  blood,  225 

conditions  indicating,  226 

in  anemia,  226 

in  carbon  monoxide  poisoning,  576 

in  collapse,  226 

in  hemophilia,  226,  227 

in  infectious  conditions,  227 

in  malnutrition,  227 

in  prostration,  227 

in  protracted  weakness,  227 

in  sepsis,  227 

in  shock,  226 

and  collapse,  251 
Lindemann's  method,  226 


Transfusion    of    blood,    Satterlee    and 

Hooker's  method,  226 
Treatment,  expectant,  61 

scope  of,  60 

specific,  60 

symptomatic,  60 
Trichinosis,  thymol  in,  117 
Trichloracetic  acid,  89 
Trichlorethyl-glycuronic  acid,  361 
Trifacial  neuralgia,  aconite  in,  236 
butyl  chloral  hydrate  in,  363 
veratrum  in,  238 

Trigeminal  neuralgia,  alcohol  in,  354 
Trimethol,  504 
Trimethyl  xanthine,  252 
Trimethyl-benzoxy-piperidine,  423 
Trimethyl-methoxy-phenol,  504 
Trimethylxanthine,  253 
Trinitrin,  239 
Trional,  364 

poisoning  from,  364,  365 
Trioxymethylanthraquinone,  131 
Trioxymethylene,  510 
Trioxypurin,  252 
Triturates,  tablet,  587 
Trituratio,  definition,  41 
Trituration,  definition,  41 
Troche,  definition,  41 
Trochiscus,  definition,  41 
Tropacocaine,  423 
Truxilline,  41 2 

Trypanosomiasis,  antimony  in,  552 
Trypsin,  27 
Tub-bath,  461 
Tuberculosis,  cod-liver  oil  in,  72 

iodides  in,  theory  of  action,  557 

mercury  succinimide  in,  521 

night-sweats  of,  sulphuric  acid  in,  88 

quinine  in,  477. 
Tuberculous  cavities,  Beck's  treatment, 

523 

laryngitis,  antipyrine  in,  469 

ulcers  of  throat,  lactic  acid  in,  89 
Tubules  of  kidneys,  functions,  451,  452 
Tully  powder,  374 

dose,  374 
Turkish  bath,  444 

Turpentine,  oil  of,  for  tape- worms,  119 
Turpeth  mineral  in  croup,  521 
Twilight  sleep,  410 
Tympanites,  carminatives  in,  105 

counterirritants  for,  78 

hormonal  in,  85 

pituitary  extract  in,  210 
Typhoid  fever,  citric  acid  in,  89 
Tyramine,  567 

dose,  568 

effect  on  circulation,  569 


ULCER,  gastric,  scarlet  red  in,  80 
of  stomach,  orthoform  in,  424 


652 


INDEX 


Ulcer,  sluggish,  burnt  alum  in,  536 

tuberculous,  of  throat,  lactic  acid  in, 

89 
Ulcus  corneae  serpens,  ethylhydrocupre- 

ine  in,  479 

Uncinaria  americana,  treatment,  117 
Unguentum,  definition,  42 

hydrargyri  as  antiseptic,  519 
dilutum  as  antiseptic,  519 
United  States  Pharmacopoeia,  45 
Urea,  diuretic  action,  455 
Uremia,  diaphoresis  in,  448 

oxygen  in,  580 

Ureteral  stone,  papaverine  in,  390 
Urethane,  366 
Urethra  disinfectants,  516 

spasm  of,  cocaine  in,  421 
Urethral  suppository,  42 
Urethritis,  copper  sulphate  in,  529 

zinc  sulphate  in,  530 
Uric  acid,  252 

Urinary  tract,  disinfectants,  517 
Urine,  constituents,  452 

of  diuresis,  450.     See  also  Diuresis. 

retention  of,  from  digitalis,  181 

suppression  of,  from  digitalis,  181 
Urothropine,  24,  512 

test,  512 

Useful  drugs,  book  of,  47 
U.  S.  P.,  45 

Utensils,  disinfectants  for,  515 
Uterine  inertia,  quinine  in,  477 

pituitary  extract  in,  210 
Uterus,  subinvolution  of,  ergot  in,  572 


VACCINES,  preservatives  for,  515 
Vagina  disinfectants,  516 
Vaginal  suppository,  42 
Vaginismus,  cocaine  in,  421 
Vaginitis,  copper  sulphate  in,  529 

zinc  sulphate  in,  530 
Vagus  system,  150 
depression,  151 
stimulation,  151 
Valerian,  393 

ammoniated  tincture  of,  107 
dose,  394 

preparations  and  doses,  394 

tincture,  dose,  394 
Valerianates,  394 
Valerianic  acid,  394 
Val let's  mass,  537 
Vapor  bath,  445 
Vaseline,  33 

in  dry  arthritis,  33 

liquid,  33,  125 

white,  33 

Vasoconstriction  from  epinephrine,  199 
Vasoconstrictors,  152 
Vasodilators,  152 
Vasomotor  reversal,  199.  569 


Vasotonin,  425 
Vegetable  astringents,  114 

cathartic  pills,  137 
Vegetables  as  cathartic  measure,  1 23 
Vehicle  for  prescription,  585 
Vein  anesthesia,  Bier's,  422 
Veins,  action  of  digitalis  on,  180 

administration  by,  55 

contraction  of,  154 

dilatation  of,  154 
Venereal  sores,  mercury  in,  519 
Venesection,  245 

action,  246 

and  transfusion  in  mercury  poisoning, 
524 

therapeutics,  246 

Venous  engorgement,  digitalis  in,  181 
Ventricle,    right,    of    heart,    action    of 

digitalis  on,  167 

Ventricular  fibrillation  from  digitalis,  171 
Veratridine,  236,  237 
Veratrine,  236,  237 

action,  238 

dose,  237 

pharmacologic  action,  237 

therapeutics,  238 
Veratrum,  236 

album,  237 

constituents,  236 

dose,  237 

fluidextract,  dose,  237 

in  eclampsia,  238 

in  trifacial  neuralgia,  238 

pharmacologic  action,  237,  238 

poisoning  from,  238 

preparations  and  doses,  237 

therapeutics,  238 

tincture,  dose,  237 

toxicology,  238 

viride,  236 
Verbs,  Latin,  590 
Vermouth  wine,  320 
Veronal,  365 

poisoning  from,  365 

toxicology,  365 
Veronal-sodium,  365 
Verworn's  theory  of  narcosis,  283 

_of  sleep,  356 
Vesicant,  72 
Vesicle-producing,  72 
Vinegar,  160 

definition,  40 
Vinum  portense,  318 

xericum,  318 

Vision,  diminished,  strychnine  in,  281 
Volatile  oil  of  mustard,  26 

oils,  34 

as  antiseptics,  504 
occurrence,  34 
Vomiting  after  anesthesia,  297 

and  nausea  of  pregnancy,  ingluvin  in, 
85 


INDEX 


653 


Vomiting   and    nausea   of   pregnancy, 
treatment,  112 

bismuth  in,  532 

bromides  in,  371 

center,  action  of  digitalis  on,  183 

cerium  in,  532 

chloroform  in,  292 

morphine  in,  387 

papaverine  in,  390 
Vulva,  itching  of,  cocaine  in,  421 
epinephrine  in,  205 


WARBURG'S  tincture,  133,  471 

without  aloes,  471 
Warts,  glacial  acetic  acid  for,  89 
lunar  caustic  for,  533 
nitric  acid  for,  87 
salicylic  acid  in,  483 
trichloracetic  acid  for,  89 
Wash,  black,  520 

lead  and  opium,  373,  525 
yellow,  520 
Washed  sulphur  to  give  bulk  and  soft 

consistency  to  feces,  1 25 
Wasting,  infantile,  thyroid  gland  in,  562 
Water,  39 

as  cathartic  measure,  1 24 
as  diaphoretic,  444 
diuretic  action,  455 
Pluto,  148 

concentrated,  148 
starch,  28 

Water-retention,  digitalis  in,  182 
Waters,  acid,  147 
alkaline,  147 
saline,  147 
alum,  147 
arsenical,  147 
bromine,  147 
chalybeate,  147 
ferruginous,  147 
iodine,  147 
lithia,  147 
mineral,  146 
effervescing,  146 
non-effervescent,  146 
non-thermal,  146 
sparkling,  146 
still,  146 
thermal,  146 
purgative,  147 
saline,  147 
sulphur,  147 
Wax,  white,  32 

yellow,  32 
Waxes,  29,  32 
Weakness,    protracted,    transfusion    of 

blood  in,   227 
Weight,  body,  dose  and,  48 
Weights  and  measures,  43 
apothecaries',  43 


Weights  and  measures,  apothecaries', 

exact  equivalents,  44 
metric,  43 

Wet  brain,  348,  350 
Wet-cupping,  247 
Whey,  84 
Whiskey,  319 
Irish,  319 
Scotch,  319 
White  arsenic,  541 
petrolatum,  33 
precipitate  ointment,  520 

as  antiseptic,  519 
vaseline,  33 
wax,  32 
wine,  318 
Whooping-cough,  antipyrine  in,  469 

bromoform  in,  372 
Wild  cherry,  fluidextract  of,  426 
infusion  of,  426 
syrup  of,  426 
Wilms'  treatment  of  mercury  poisoning, 

524 
Wine,  definition,  40 

of  antimony,  552 

of  coca,  therapeutics,  420 

of  colchicum  root,  487 
seed,  487 

white,  318 
Wines,  317 

dry,  318 

fortified,  318 

heavy,  318 

light,  318 

Madeira,  318 

port,  318 

red,  318 

sherry,  318 

sparkling,  318 

strong,  318 

sweet,  318 

Vermouth,  320 
Wood  alcohol,  355 

naphtha,  355 
Wood-charcoal,  109,  no 
Worms,  intestinal,  anthelmintics  for,  115 

pin-,  quinine  in,  476 
remedies  for,  116 

round-,  remedies  for,  116 

tape-,  dwarf,  remedies  for,  119 
remedies  for,  119 

thread-,  remedies  for,  116 
Wormseed,  Levant,  116 
Wormwood,  320 

Wounds,   disinfection   of,   Dakin-Carrel 
treatment,  495 

open,  disinfectants  in,  517 
Wrist-drop  in  lead  poisoning,  527 

XANTHINE,  252 
dimethyl,  252 
trimethyl,  252 


654 

YELLOW  jasmine,  428 

wash,  520 

wax,  32 
Yerba  santa,  109,  425 

syrup  of,  109 
Yohimbine,  424 
Young's  rule  for  dosage,  49 

ZINC,  530 

as  antiseptic  and  disinfectant,  500 
carbonate,  530 


INDEX 


Zinc  chills,  530 

chloride,  530 

irritant  salts,  530 

ointment,  530 

oxide,  530 

poisoning,  530 

precipitated  carbonate,  530 

soothing  salts,  530 

stearate,  530 

sulphate,  530 
Zincum,  530 


SURGERY 


and 


ANATOMY 


W.  B.  SAUNDERS   COMPANY 


Elsberg's  Surgery  of  Spinal  Cord 

Surgery  of  the  Spinal  Cord.  By  CHARLES  A.  ELSBERG,  M.  D., 
Professor  of  Clinical  Surgery,  New  York  University  and  Bellevue 
Hospital  Medical  School.  Octavo  of  330  pages,  with  153  illustrations, 

Cloth,     $5.00    net.  Published  July,  1916 

There  is  no  other  book  published  like  this  by  Dr.  Elsberg.  It  gives  you  in 
clear  definite  language  the  diagnosis  and  treatment  of  all  surgical  diseases  of  the 
spinal  cord  and  its  membranes,  illustrating  each  operation  with  original  pictures. 
Because  it  goes  so  thoroughly  into  symptomatology,  diagnosis,  and  indications  for 
operation  this  work  appeals  as  strongly  to  the  general  practitioner  and  neurologist 
as  to  the  surgeon. 


Cullen  on  the  Umbilicus 

Embryology,    Anatomy,    and    Diseases    of    the    Umbilicus.      By 

THOMAS  S.   CULLEN*,  M.  B.,  Associate    Professor  of  Gynecology,  Johns 
Hopkins    University.         Octavo    of  680   pages,  with   269  illustrations. 

Cloth,   $7oO  net.  Published  May,  1916 

In  Dr.  Cullen' s  ne\v  work  you  get  chapters  on  embryology,  anatomy,  infections 
in  the  newborn,  hemorrhage,  granulation  tissue  at  the  umbilicus,  umbilical  polypi, 
gastric  mucosa  at  the  umbilicus,  Meckel's  diverticulum,  intestinal  cysts,  patent 
omphalomesenteric  duct,  prolapsus  of  the  bowel,  concretions,  abscess,  etc. 

The   editions   you   find   here   may  not   be  the   latest. 
Write  us  about  any  books  in  which  you  are  interested 


SAUNDERS1  BOOKS    ON 


Albee's  Bone-Graft  Surgery 

Bone-graft  Surgery.  By  FRED  H.  ALBEE,  M.  D.,  Professor  of 
Orthopedic  Surgery  at  the  New  York  Post-graduate  Medical  School. 
Octavo  of  417  pages,  with  329  text-illustrations  and  3  colored  plates. 

Cloth,    $6.5O   net.  Published  November,  1915 

ORIGINAL 

This  book  presents  Dr.  Albee's  original  applied  technic  for  bone-graft  work.  The  suc- 
cessful outcome  of  any  procedure  to  restore  the  skeletal  architecture  depends  not  only  upon 
a  proper  operative  technic,  but  in  many  cases  in  a  greater  degree  upon  the  skill  with  which 
the  postoperative  external  fixation  dressing  is  applied  and  in  the  convalescent  management 
of  the  case.  Dr.  Albee  here  gives  you  his  own  successful  technic  and  his  own  methods  of 
dressing  and  management,  all  illustrated  with  original  pictures. 

Dr.  Albee  is  a  firm  believer  in  the  autogenous  graft,  and  in  making  it  he  uses  the  most 
improved  instruments  and  tools,  all  of  which  are  shown  you,  and  their  use  in  actual  work. 
This  is  the  only  book  going  fully  into  this  important  qnestion  of  bone  surgery,  a  field  of  sur- 
gical endeavor  that  is  attracting  pronounced  attention  over  the  entire  surgical  world. 


Smithies  and  Ochsner's 
Cancer  of  the  Stomach 

Cancer  of  the  Stomach.  By  FRANK  SMITHIES,  M.  D.,  Gastro- 
enterologist  to  Augustana  Hospital,  Chicago.  With  a  chapter  on  the 
Surgical  Treatment  of  Gastric  Cancer,  by  ALBERT  J.  OCHSNER,  M.  D., 
Professor  of  Clinical  Surgery,  University  of  Illinois.  Octavo  of  500 

pages,  illustrated.        Cloth,  $5.75  llCt.  Published  January,  1916 

A  STUDY  OF  921  CASES 

This  work  gives  you  the  information  Cleaned  from  a  study  of  921  operatively  and  path 
ologically  demonstrated  cases  of  gastric  cancer. 

This  new  work  is  the  first  monograph  upon  this  subject  for  more  than  a  decade,  and 
represents  some  ten  years'  study  of  cases  at  the  University  Hospital  of  Ann  Arbor,  The  Mayo 
Clinic,  and  the  Augustana  Hospital  of  Chicago.  The  wonderful  advances  made  within  this 
time  are  of  the  greatest  importance  to  the  clinician,  the  pathologist,  and  the  surgeon.  Dr. 
Smithies  presents  these  advances  in  a  most  practical  way.  The  chapter  on  Operative  Treat- 
ment, by  Dr.  Ochsner,  gives  you  the  most  approved  and  successful  technic,  illustrating  the 
various  operations  with  original  pictures. 


SURGERY  AND  ANATOMY 


Hornsby   and    Schmidt's 
The  Modern  Hospital 

The  Modern  Hospital.  Its  Inspiration ;  Its  Construction ;  Its 
Equipment;  Its  Mangement.  By  JOHN  A.  HORNSBY,  M.  D.,  Secre- 
tary, Hospital  Section,  American  Medical  Association ;  and  RICHARD 
E.  SCHMIDT,  Architect.  Large  octavo  of  644  pages,  with  207  illus- 
trations. Cloth,  $7-00  net.  March,  1913 
HOSPITAL  EFFICIENCY 

"  Hornsby  and  Schmidt"  tells  you  just  exactly  how  to  plan,  construct,  equip, 
and  manage  a  hospital  in  all  its  departments,  giving  you  every  detail.  It  gives 
you  exact  data  regarding  heating,  ventilating,  plumbing,  refrigerating,  etc. — and 
the  costs.  It  tells  you  how  to  equip  a  modern  hospital  with  modern  appliances. 
It  tells  you  what  you  need  in  the  operating  room,  the  wards,  the  private  rooms, 
the  dining  room,  the  kitchen — every  division  of  hospital  housekeeping.  It  gives 
you  the  duties  of  the  directors,  the  superintendent,  the  various  staffs,  their  relations 
to  each  other.  It  tells  you  all  about  nurses'  training-schools — their  management, 
curriculum,  rules,  regulations,  etc.  It  gives  you  hundreds  of  valuable  points  on 
the  business  management  of  hospitals — large  and  small. 

Howell  Wright,  Superintendent  City  Hospital,  Cleveland 

"  To  me  the  book  is  invaluable.  I  have  a  copy  on  my  desk  and  scarcely  a  day  passes 
but  what  I  consult  it  and  find  what  I  want." 

Allen's  Local  Anesthesia 

Local  Anesthesia.  By  CARROLL  W.  ALLEN,  M.  D.,  Instructor  in 
Clinical  Surgery  at  Tulane  University  of  Louisiana.  Octavo  of  608 
pages,  illustrated.  Cloth.  $6.00  net. 

COMPLETE  IN  EVERY  PARTICULAR 

This  is  a  complete  work  on  this  subject.  You  get  the  history  of  local 
anesthesia,  a  chapter  on  nerves  and  sensation,  giving  particular  attention  to  pain 
— what  it  is  and  its  psychic  control.  Then  comes  a  chapter  on  osmosis  and 
diffusion.  Each  local  anesthetic  is  taken  up  in  detail,  giving  very  special  atten- 
tion to  cocain  and  novocain,  pointing  out  the  action  on  the  nervous  system,  the 
value  of  adrenalin,  paralysis  caused  by  cocain  anesthesia,  control  of  toxicity. 
You  get  Crile's  method  of  administering  adrenalin  and  salt  solution,  the  exact 
way  to  produce  the  intradermai  wheal,  to  pinch  the  flesh  for  the  insertion  of  the 
needle — all  shown  you  step  by  step.  You  get  full  discussions  of  paraneural, 
intraneural,  and  spinal  analgesia,  intravenous  and  intra-arterial  anesthesia,  and 
Hackenbuck's  regional  anesthesia  by  circumferential  injections.  You  get  indica- 
tions, contraindications,  an  article  on  anoci-associaticn,  with  Crile's  technic  for 
producing  anesthesia.  Then  the  production  of  local  anesthesia  in  the  various 
regions  is  taken  up  in  detail.  Spinal  analgesia  and  epidural  injections  are  con- 
sidered in  a  monogragh  of  45  pages.  Published  October,  1914 


SAUNDERS'    BOOKS    ON 


The   New  Keen's    Surgery 

Surgery:  ITS  PRINCIPLES  AND  PRACTICE.  Written  by  8 1  eminent 
specialists.  Edited  by  W.  W.  KEEN,  M.  D.,  LL.D.,  HON.  F.R.C.S.,  ENG. 
AND  EDIN.,  Emeritus  Professor  of  the  Principles  of  Surgery  and  of 
Clinical  Surgery  at  the  Jefferson  Medical  College.  Six  octavos  of  1050 
pages  each,  containing  3100  original  illustrations,  157  in  colors.  Per 
volume:  Cloth,  37.50  net. 

VOLUME   VI  GIVES   YOU   THE   NEWEST   SURGERY 

ALL  THE  ADVANTAGES  OF  A  REVISION  AT  ONE-FIFTH  THE  COST 

We  have  issued  a  Volume  VI  of  "  Keen  " — the  volume  of  the  newest  surgery- 
In  this  way  you  get  all  the  advantages  of  a  complete  and  thorough  revision  at  but 
one-fifth  tJu-  cost.  It  makes  Keen's  Surgery  the  best,  the  most  up-to-date  surgery 
on  the  market. 

In  this  sixth  volume  you  get  the  newest  surgery — both  general  and  special — 
from  the  pens  of  those  same  international  authorities  who  have  made  the  success 
of  Keen's  Surgery  world-wide.  Kach  man  has  searched  for  the  new,  the  really 
ttscfu/,  in  his  particular  field,  and  he  gives  it  to  you  here.  Here  you  get  the 
newest  surgery,  and  fully  illustrated.  Then,  further,  you  get  a  complete  index  to 
the  entire  six  volumes,  covering  125  pages,  but  so  arranged  that  reference  to  it  is 
extremely  easy.  If  you  want  the  newest  surgery,  you  must  turn  to  the  new 
"  Keen  ' '  for  it.  Volunu-  VI  published  March,  1913 


Keen's  War  Wounds 

Treatment  of  War  Wounds.  By  \V.  \V.  KEEN,  M.  D.,  LL.D., 
Major,  Medical  Reserve  Corps,  U.  S.  Army.  121110  of  169  pages,  illus- 
trated. Cloth,  $1.75  net  Published  August,  101 7 

TREATMENTS  BEING  USED  IN  FRANCE 

This  work,  based  on  a  report  to  the  National  Research  Council,  revieus 
the  latest  information.  It  is  obtained  by  direct  communication  from  the  war 
hospitals  in  France.  It  gives  the  formulas,  preparation,  application,  and  results 
of  Carrel-Dakin's  solution,  eupad.  eusol.  and  other  antiseptics  being  used  with 
such  marked  success.  It  takes  up  the  removal  of  toreign  bodies,  treatment 
and  prevention  of  tetanus,  gas  infection  and  gas  gangrene,  head  wounds,  ab- 
dominal wounds,  ambrine  and  \o.  7  paraffin  for  burns.  It  is  an  important 
book,  instructive  from  cover  to  cover. 


SURGERY  AND   ANATOMY 


Crandon  and  Ehrenfried's 
Surgical    After-treatment 

Surgical  After-treatment.  A  Manual  of  the  Conduct  of  Surgical 
Convalescence.  By  L.  R.  G.  CRANDON,  M.  D.,  Assistant  in  Surgery, 
and  ALBERT  EHRENFRIED,  M.  D.,  Assistant  in  Anatomy,  Harvard  Medi- 
cal School.  Octavo  of  831  pages,  with  265  original  illustrations. 

Cloth,  $6.OO  net,  Published  May,  1912 

SECOND  EDITION— PRACTICALLY  REWRITTEN 

This  work  tells  how  best  to  manage  all  problems  and  emergencies  of  surgical 
convalescence  from  recovery-room  to  discharge.  It  gives  all  the  details  com-, 
pletely,  definitely,  yet  concisely,  and  does  not  refer  the  reader  to  some  other 
work  perhaps  not  then  available.  The  post-operative  conduct  of  all  operations 
is  given,  arranged  alphabetically  by  regions.  A  special  feature  is  the  elaborate 
chapter  on  Vaccine  Therapy,  Immunization  by  Inoculation  and  Specific  Sera, 
by  Dr.  George  P.  Sanborn,  a  disciple  of  Sir  A.  E.  Wright.  The  text  is  illustrated. 

The  Therapeutic  Gazette 

"The  book  is  one  which  can  be  read  with  much  profit  by  the  active  surgeon  and  will  be 
generally  commended  by  him." 


Papers  from   the   Mayo   Clinic 

Collected  Papers  of  the  Mayo  Clinic.  By  WILLIAM  J.  MAYO,  M.  D., 
CHARLES  II.  MAYO,  M.  D.,  and  their  ASSOCIATES  at  The  Mayo  Clinic, 
Rochester,  Minn.  Papers  of  1905-1909.  1910,  1911,1912,  1913.  Each 
an  octavo  of  about  800  pages,  illustrated.  Per  volume:  Cloth,  $5.50 
net.  1916  Papers  (June,  191?):  Cloth,  $6.50  net. 

THE  NEWEST  SURGICAL  METHODS 

These  volumes  give  you  all  the  clinical  teachings,  all  the  important  papers  of 
W.  J.  and  C.  II.  Mayo  and  their  associates  at  The  Mayo  Clinic.  They  give  you 
the  advances  in  operative  technir.,  in  methods  of  diagnosis  as  developed  at  this 
great  clinic.  This  ne\v  volume,  although  called  the  igj6  -volume,  gives  you  many 
papers  that  did  not  appear  until  •;>'.•//  info  1017,  quite  a  few  being  scheduled  for  as 
late  as  May  and  June.  You  should  acid  this  volume  to  your  Mayo  files. 

Bulletin  Medical  and  Chirurgical  Faculty  of  Maryland 

"  Much  of  the  work  done  at  the  Mayo  Clinic  and  re  on  \,r<\  in  these  papers  has  been  epoch- 
making  in  character.  *  *  *  Represents  a  most  substantial  block  of  modern  surgical  progress." 

A  Collection  of  Papers  (published  previous  to  1909).  By 
WILLIAM  J.  MAYO,  M.  D.,  and  CHARLES  H.  MAYO,  M.  D.  Two  octavos 
of  525  pages  each,  illustrated.  Per  set  :  Cloth,  $10.00  net 


SAUNDERS'    BOOKS   ON 


Moorhead's 
Traumatic    Surgery 

Traumatic  Surgery.  By  JOHN  J.  MOORHEAD,  M.  D.,  Associate 
Professor  of  Surgery,  New  York  Post-Graduate  Medical  School  Lnd 
Hospital.  Octavo  of  760  pages,  with  520  original  line-drawings. 

Published  February,  1917.        Cloth,  $7-OO  net. 

FOUR  PRINTINGS  IN  TEN  MONTHS 

Here  is  a  new  book  on  just  this  side  of  your  practice — a  work  for  the  general 
practitioner,  the  surgeon,  the  mining,  railroad  and  industrial  physician,  those 
having  to  do  with  Compensation  Law,  accident  insurance  and  claims,  and  legal 
medicine.  To  those  medical  men  engaged  in  or  preparing  for  military  service 
this  work  is  proving  of  great  value.  For  instance,  it  gives  you  at  first  hand 
the  open  air  and  sunlight  treatment  of  wounds  and  Dakin's  solution,  its  formula 
and  application — treatments  the  European  War  has  brought  forward  so  em- 
phatically. 


DaCosta's  Modern  Surgery 

Modern  Surgery — GENERAL  AND  OPERATIVE.  By  JOHN  CHALMERS 
DACOSTA,  M.  D.,  Samuel  D.  Gross  Professor  of  Surgery,  Jefferson 
Medical  College,  Philadelphia.  Octavo  of  1515  pages,  with  1085  illus- 
trations. April,  1914  Cloth,  $6.oo  net. 

SEVENTH    EDITION 

A  surgery,  to  be  of  the  maximum  value,  must  be  up  to  date,  must  be  com- 
plete, must  have  behind  its  statements  the  sure  authority  of  experience,  must  be  so 
arranged  that  it  can  be  consulted  quickly;  in  a  word,  it  must  be  practical  and 
dependable.  Such  a  surgery  is  DaCosta's.  Always  an  excellent  woik,  for  this 
edition  it  has  been  very  materially  improved  by  the  addition  of  new  matter  to  the 
extent  of  over  250  pages  and  by  a  most  thorough  revision  of  the  old  matter. 
Many  old  cuts  have  been  replaced  by  new  ones,  and  nearly  150  additional  illus- 
trations have  been  added. 


Rudolph  Matas,  M.  D.,  Professor  of  Surgery,  TuLine  University  of  Louisiana. 

"  This  edition  is  destined  to  rank  as  high  as  its  predecessors,  which  have  placed  the  learned 
author  in  the  fore  of  text-book  writers.  The  more  I  scrutinize  its  pages  the  more  I  admire  the 
marvelous  capacity  of  the  author  to  compress  so  much  knowledge  vn  so  small  a  space." 


SURGERY  AND  ANATOMY 


Scrudder's 
Treatment  of  Fractures 

WITH  NOTES  ON  DISLOCATIONS 

The  Treatment  of  Fractures :  with  Notes  on  a  few  Common 
Dislocations.  By  CHARLES  L.  SCUDDER,  M.  D.,  Assistant  Professor  of 
Surgery  at  Harvard  Medical  School.  Octavo  of  734  pages,  with  1057 
original  illustrations.  Polished  Buckram,  $6.00  net. 

Published  June,  1915 

THE  NEW  (8th)  EDITION.  ENLARGED 
WITH  1057  ILLUSTRATIONS 


The  fact  that  this  work  has  attained  an  eighth  edition  indicates  its  practical 
value.  In  this  edition  Dr.  Scudder  has  made  numerous  additions  throughout 
the  text,  and  has  added  many  new  illustrations,  greatly  enhancing  the  value  of 
the  work.  In  every  way  this  new  edition  reflects  the  very  latest  advances  in  the 
treatment  of  fractures. 

J.  F.  Binnie,  M.D.,  University  of  Kansas 

"  Scudder's  Fractures  is  the  most  successful  book  on  the  subject  that  has  ever  been  pub., 
lished.     I  keep  it  at  hand  regularly." 


Scudder's  Tumors  of  the  Jaws 

Tumors  of  the  Jaws.  By  CHARLES  L.  SCUDUER,  M.  D.,  Assistant 
Professor  of  Surgery  at  Harvard  Medical  School.  Octavo  of  395  pages, 
with  353  illustrations,  6  in  colors.  Cloth,  $6.50  net. 

Published  February,  1912 
WITH  NEW  ILLUSTRATIONS 

Dr.  Scudder  in  this  book  tells  you  how  to  determine  in  each  case  the  farm  of 
new  growth  present  and  then  points  out  the  best  treatment.  As  the  tendency  of 
malignant  disease  of  the  jaws  is  to  grow  into  the  accessory  sinuses  and  toward 
the  base  of  the  skull,  an  intimate  knowledge  of  the  anatomy  of  these  sinuses  is 
essential.  Dr.  Scudder  has  included,  therefore,  sufficient  anatomy  and  a  number 
of  illustrations  of  an  anatomic  nature.  Whether  general  practitioner  or  surgeon, 
you  need  this  new  book  because  it  gives  you  just  the  information  you  want. 


SOUNDERS'   BOOKS  ON 


Cotton's 

Dislocations    arid    Joint    Fractures 

Dislocations  and  Joint  Fractures.  By  FREDERIC  JAY  COTTON,  M.  D-, 
First  Assistant  Surgeon  to  the  Boston  City  Hospital.  Octavo  of  654 
pages,  with  I2OI  original  illustrations.  Cloth,  $6.00  net. 

Published  July,  1910 
TWO  PRINTINGS  IN  EIGHT  MONTHS 

Dr.  Cotton's  clinical  and  teaching  experience  in  this  field  has  especially  fitted 
him  to  write  a  practical  work  on  this  subject.  He  has  written  a  book  clear  and 
definite  in  style,  systematic  in  presentation,  and  accurate  in  statement.  The 
illustrations  possess  the  feature  of  showing  just  those  points  the  author  wishes  to 
emphasize.  This  is  made  possible  because  the  author  is  himself  the  artist. 

Boston  Medical  and  Surgical  Journal 

"  The  work  is  delightful,  spirited,  scholarly,  and  original,  and  is  not  only  a  book  of  refer- 
ence, but  a  book  for  casual  reading.  It  brings  the  subject  up  to  date,  a  feat  long  neglected." 


The  Surgical  Clinics  of  Chicago 

The  Surgical  Clinics  of  Chicago.  By  leading  Chicago  surgeons. 
Issued  serially,  one  octavo  of  2OO  pages,  illustrated,  every  other  month 
(six  volumes  a  year).  Per  Clinic  Year  (February  to  December):  Cloth, 
$14.00  net;  Paper,  $10.00  net. 

SURGERY  FROM  THE  CLINICAL  SIDE 


This  new  bi-monthly  considers  all  departments  of  surgery  from  the  clinical 
side,  giving  particular  emphasis  to  differential  diagnosis  and  treatment.  It  gives 
you  the  actual  word  for  word  clinics  of  40  great  teacher-surgeons  of  Chicago, 
representing  ail  the  important  hospitals  of  that  great  center  of  post-graduate  instruc- 
tion. You  get  the  day-in  and  day-out  teachings  of  these  men.  You  get  their 
tried  and  proved  methods  of  diagnosis;  their  operative  technic;  their  plans  of  man- 
agement; the  benefit  of  their  years  of  experience,  with  a  wealth  of  clinical  material 
unequalled  for  variety  and  quantity.  Add  to  the  matter  of  the  books  the  illustrations 
by  Tom  Jones,  and  the  result  is  practically  applied,  absolutely  fresh  teachings,  em- 
bodying all  the  new  methods. 


SURGERY  AND  ANATOMY 


Kelly  &  Noble's  Gynecology 
arw  Abdominal  Surgery 

Gynecology  and  Abdominal  Surgery.  Edited  by  HOWARD  A. 
KELLY,  M.D.,  Professor  of  Gynecology  in  Johns  Hopkins  University; 
and  CHARLES  P.  NOBLE,  M.D.,  formerly  Clinical  Professor  of  Gyne- 
cology in  the  Woman's  Medical  College,  Philadelphia.  Two  imperial 
octavo  volumes  of  950  pages  each,  containing  880  original  illustrations, 
some  in  colors.  Per  volume:  Cloth,  $8.00  net. 

Volume  I  published  May,  1907;  Volume  II  published  June,  19CS 

WITH  880  ILLUSTRATIONS— TRANSLATED  INTO  SPANISH 

This  work  possesses  a  number  of  valuable  features  not  to  be  found  in  any 
Other  publication  covering  the  same  fields.  It  contains  a  chapter  upon  the  bac- 
teriology and  one  upon  the  pathology  of  gynecology,  and  a  large  chapter  devoted 
entirely  to  medical  gynecology,  written  especially  for  the  physician  engaged  in 
general  practice.  Abdominal  surgery  proper,  as  distinct  from  gynecology,  is 
fully  treated,  embracing  operations  upon  the  stomach,  intestines,  liver,  bile-ducts, 
pancreas,  spleen,  kidneys,  ureter,  bladder,  and  peritoneum. 

American  Journal  of  Medical  Sciences 

"  It  is  needless  to  say  that  the  work  has  been  thoroughly  done ;  the  names  of  the  authors 
and  editors  would  guarantee  this,  but  much  maybe  said  in  praise  of  the  method  of  presentation, 
and  attention  may  be  called  to  the  inclusion  of  matter  not  to  be  found  elsewhere.'1 


Cushing's  Brain  Tumors 

Tumors  of  the  Nervus  Acusticus  and  the  Syndrome  of  the 
Cerebellopontile  Angle.  By  HARVKV  GUSHING.  M.  D.,  Surgeon-in- 
Chief,  Peter  Bent  Brigham  Hospital,  Boston.  Octavo  of  296  pages, 

With    202   illustrations.        Cloth,   S;.OO  net.  Published  November,  1917 

A  STUDY  OF  65  CASES 

Dr.  dishing  presents  here  an  exhaustive  study  of  tumors  of  the  acoustic  nerve. 
He  gives  you  his  o\vn  technic,  and  the  results  of  study  and  observation  of  some 
thirty  cases — a  thorough  presentation  of  the  subject,  embracing  history,  analysis 
of  symptoms,  physical  examination,  morphology,  histology,  and  operative  technic. 
You  are  given  not  only  the  surgical  aspects,  but  the  historical,  symptomatic,  and 
pathologic  as  well.  The  illustrations  are  particularly  noteworthy. 


io  SAUNDERS'    BOOKS    ON 

Moynihan's 
Abdominal    Operations 

Abdominal  Operations.  By  SIR  BERKELEY  MOYNIHAN,  M.  S. 
(LONDON),  F.  R.  C.  S.,  of  Leeds,  England.  Two  octavos,  totaling 
nearly  1000  pages,  with  385  illustrations.  Per  set:  Cloth,  $11.00  net. 

Published  October,  1914 

THIRD  EDITION.  ENLARGED 

This  new  (jd)  edition  was  so  thoroughly  revised  that  the  work  had  to  be  reset  from 
cover  to  cover.  Over  150  pages  of  new  matter  and  some  85  new  illustrations  were  added, 
making  385  illustrations,  5  of  them  in  colors — really  an  atlas  of  abdominal  surgery.  This 
work  is  a  personal  record  of  Moynihan'  s  operative  work.  You  get  his  own  successful  methods 
of  diagnosis.  You  get  his  own  technic,  in  every  case  fully  illustrated  with  handsome  pic- 
tures. You  get  the  bacteriology  of  the  stomach  and  intestines,  sterilization  and  preparation 
of  patient  and  operator.  You  get  complications,  sequels,  and  after-care.  Then  the  various 
operations  are  detailed  with  forceful  clearness,  discussing  first  gastric  operations,  following 
with  intestinal  operations,  operations  upon  the  liver,  the  pancreas,  the  spleen.  Two  new 
chapters  added  in  this  edition  are  excision  of  gastric  ulcer  and  complete  gastrectomy,  giving 
the  latest  developments  in  these  operative  measures. 


Moynihan's  Duodenal  Ulcer 

Duodenal  Ulcer.  By  SIR  BERKELEY  MOYNIHAX,  M.  S.  (LONDON),  F.  R.  C.  S., 
Leeds,  England.  Octavo  of  486  pages,  illustrated.  Cloth,  $5.00  net. 

Published  March,  1912 

For  the  practitioner,  who  first  meets  with  these  cases,  Mr.  Moynihan  fixes  the  diagnosis 
with  precision,  so  that  the  case,  if  desired,  may  be  referred  in  the  early  stage  to  the  sur- 
geon. The  surgeon  finds  here  the  newest  and  best  technic  as  used  by  one  of  the  leaders 
in  this  field. 

"  Easily  the  best  work  on  the  subject ;  coming,  as  it  docs,  from  the  pen  of  one  of  the  mas- 
ters of  surgery  of  the  upper  abdomen,  it  may  be  accepted  as  authoritative." — London  Lancet. 

Moynihan's  War  Surgery 

American  Addresses  on  War  Surgery.  By  SIR  BERKELEY  MOYNIHAN, 
M.  S.,  F.  R.  C.  S.,  Surgeon  General,  A.  M.  S.  121110  of  143  pages.  Cloth, 
Si. "5  net.  Published  November,  1917 

The  experiences  of  this  English  surgeon,  who  has  been  in  active  service  since  the  very 
beginning  of  the  war,  are  contained  in  these  lectures  delivered  on  his  recent  visit  to 
this  country.  He  gives  you  treatments  of  war  wounds — preparation,  technic  of  use,  and 
relative  values  of  Carrel-Dakin's  antiseptic,  Uipp,  Wright's  physiologic  solution,  Ruth- 
erford Morison's  method — repair  of  injuries  to  lungs,  pleura,  knee-joint,  and  periph- 
eral nerve.-.  He  gives  you  here  a  vital  message  from  the  front. 


SURGER  Y  AND  ANA  TOMY  1 1 

Fenger  Memorial  Volumes 

Fenger  Memorial  Volumes.  Edited  by  LUDVIG  HEKTOEX,  M.  D., 
Rush  Medical  College,  Chicago.  Two  octavos  of  525  pages  each.  Per 

Set  :    Cloth,  $  I  5  .OO  net.  Published  May,  1912 

LIMITED  EDITION 

These  handsome  volumes  consist  of  all  the  important  papers  written  by  the  late 
Christian  Fenger,  for  many  years  professor  of  surgery  at  Rush  Medical  College, 
Chicago.  Not  only  the  papers  published  in  English  are  included,  but  also  those 
which  originally  appeared  in  Danish,  German,  and  French. 

The  name  of  Christian  Fenger  typifies  thoroughness,  extreme  care,  deep  re- 
search, and  sound  judgment.  His  contributions  to  the  advancement  of  the  world's 
surgical  knowledge  are  indeed  as  valuable  and  interesting  reading  to-day  as  at 
the  time  of  their  original  publication.  They  are  pregnant  with  suggestions. 
Fenger' s  literary  prolificacy  may  be  judged  from  this  memorial  volume — over 
jooo  pages. 

Owen's  Treatment  of  Emergencies 

The  Treatment  of  Emergencies.  By  HUBLEV  R.  OWEN,  M.  D., 
Surgeon  to  the  Philadelphia  General  Hospital.  Octavo  of  350  pages, 
with  249  illustrations.  Published  June,  1917  Cloth,  $2.00  net. 

METHODS  AND  PRINCIPLES 

Dr.  Owen's  book  gives  you  not  only  the  actual  technic  of  the  procedures, 
but  also  the  underlying  principles  of  the  treatments,  and  the  reason  why  a 
particular  method  is  advised.  You  get  chapters  on  fractures  of  all  kinds,  con- 
tusions, and  wounds.  Particularly  strong  is  the  chapter  on  gunshot  wounds, 
which  gives  the  new  treatments  that  the  great  European  War  has  developed. 
You  get  the  principles  of  hemorrhage,  together  with  it's  constitutional  and  local 
treatments.  You  get  chapters  on  sprains,  dislocations,  burns,  sunburn,  chilblain, 
asphyxiation,  convulsions,  hysteria,  apoplexy,  exhaustion,  opium  poisoning, 
uremia,  electric  shock,  bandages,  and  a  complete  discussion  of  the  various 
methods  of  artificial  respiration,  including  mechanical  devices. 


Radasch's  Anatomy 

Manual  of  Anatomy.  By  HENRY  E.  RADASCH,  M.  D.,  Assistant 
Professor  of  Histology  and  Biology,  Jefferson  Medical  College.  Octavo 
of  489  pages,  with  329  illustrations.  Cloth,  $3.50  net.  Published  August,  1917 

Dr.  Radasch's  new  handbook  is  complete  in  both  text  and  illustrations. 
Every  effort  has  been  taken  to  make  the  study  of  anatomy  both  easy  and  in- 
teresting, the  many  illustrations  contributing  markedly  to  this  end. 


AND   ANATOMY 


Bryan's  Surgery 

Principles  of  Surgery.  By  \V.  A.  BRYAN,  M.  D.,  Professor  of  Surgery 
and  Clinical  Surgery  at  Yanderbilt  University,  Nashville.  Octavo  of  677 
pages,  with  224  original  illustrations.  Cloth,  $4.00  net. 

Dr.  Bryan  here  gives  you  facts,  accurately  and  concisely  stated,  without  which  no 
modern  practitioner  can  do  modern  work.  He  shows  you  in  a  most  practical  way  the 
relations  between  surgical  pathology  and  the  resultant  symptomatology,  and  points  out 
the  influence  such  information  has  on  treatment.  Published  November,  1913 

Mumford's  Practice  of  Surgery 

The  Practice  of  Surgery.  By  JAMES  G.  MUMFORD,  M.  D.,  Instructor  in 
Surgery,  Harvard  Medical  School.  Octavo  of  1032  pages,  with  68 1  illus- 
trations. Second  Edition  published  June,  1914.  Cloth,  #7.00  net. 


Fowler's    Operating    Room  Third  Edition,  Reset 

The  Operating  Room  and  the  Patient.  By  RUSSELL  S.  FOWLER,  M.  D., 
Surgeon  to  the  German  Hospital,  Brooklyn,  New  York.  Octavo  of  611 
pages,  illustrated.  Published  March,  1913.  Cloth,  $3.50  net. 

Whiting's  Bandaging 

Bandaging.  By  A.  D.  WHITING,  M.  D.,  Instructor  in  Surgery  at  the  Uni- 
versity of  Pennsylvania.  I2mo  of  151  pages,  with  117  illustrations.  Cloth, 
51.25  net.  Published  November,  1915 

Nancrede's  Essentials  of  Anatomy  Eighth  Edition 

Essentials  of  Anatomy,  including  the  Anatomy  of  the  Viscera.  By  CHAS. 
B.  NANCREUK,  M.D.,  Professor  of  Surgery  and  of  Clinical  Surgery,  University 
of  Michigan,  Ann  Arbor.  Crown  octavo,  430  pages;  154  cuts.  With  an 
Appendix  containing  over  60  illustrations.  Based  on  Gray  s  Anatomy. 
Published  October,  1911.  Cloth,  $1.25  net.  In  Sanndcrs  Question  Compends. 

Martin's  Essentials  of  Surgery  seventh  Edition 

Essentials  of  Surgery.  Containing  also  Venereal  Diseases,  Surgical  Land- 
marks and  Minor  and  Operative  Surgery,  and  a  complete  description,  with 
illustrations,  of  the  Handkerchief  and  Roller  Bandages.  By  EDWARD 
MAKIIX,  A.  M.,  M.  I).,  Professor  of  Clinical  Surgery,  University  of  Pennsyl- 
vania, etr.  Crown  octavo,  338  pages,  illustrated. 
Published  1897.  Cloth,  $1.25  net.  Iii  Siuiinlers  Question 


Metheny's  Dissection  Methods 

Dissection  Methods  and  Guides.  P-y  DAVID  GKKGC;  MI-TIIF.XY,  M.  D., 
I..  K.  C.  P.,  I,.  R.  C.  S.  <T.Dix.),  I..  F.  P.  S.  ((ii.AS.),  Associate  in  Anatomy, 
Jefferson  Medical  College,  Philadelphia.  Octavo  of  131  pages,  illustrated. 
Published  November,  1914  .  Cloth,  5  1  .  2  ;  net. 


SUR  GER  Y  A  ND  A  NA  TO  MY  1 3 

Crile  and  Lower's  Anoci-Association 

Anoci=Association.  By  GEORGE  W.  CHILE,  M.  D.,  Professor  of  Surgery, 
and  WI-LLIAM  E.  LOWER,  M.  D.,  Associate  Professor  of  Genito-Urinary  Sur- 
gery, Western  Reserve  University.  275  pages,  illustrated.  Cloth,  $3.00  net. 

Anoci-association  is  the  new  way  of  anesthetizing.  It  prevents  shock,  it  robs  surgery 
of  its  harshness,  it  diminishes  postoperative  mortality,  it  lessens  the  likelikood  of 
nausea,  vomiting,  gas-pains,  backache,  nephritis,  pneumonia,  and  other  postopera- 
tive complications.  You  get  anoci-association  and  blood-pressure  and  the  technic 
of  nitrous-oxid-oxygen  anesthesia.  Published  July,  1914 

Crile's  The  Kinetic  Drive 

The  Kinetic  Drive:  Its  Phenomena  and  Control.  By  GEORGE  W.  CRILE, 
M.  D.,  Professor  of  Surgery,  Western  Reserve  University,  Cleveland.  Octavo 
of  71  pages,  illustrated.  Published  May,  1916  Cloth,  $2.00  net. 

In  this  book  Dr.  Crile  analyzes  the  mechanism  by  which  the  present-day  industrial 
and  commercial  "speeding''  is  accomplished,  and  relates  it  to  the  speeding  due  to 
other  stimuli,  such  as  infections,  auto-intoxication,  physical  injury,  etc. 

Keen's  Addresses  and  Other  Papers 

Addresses  and  Other  Papers.  Delivered  by  WILLIAM  W.  KEEN,  M.  b.; 
LL.D.,  F.  R.  C.  S.  (Hon.),  Professor  of  the  Principles  of  Surgery  and  of  Clin 
ical  Surgery,  Jefferson  Medical  College,  Philadelphia.  Octavo  volume  of 
441  pages,  illustrated.  Published  May,  1905  Cloth,  $3.75  net. 

tteen  on  the  Surgery  of  Typhoid 

The  Surgical  Complications  and  Sequels  of  Typhoid  Fever.     By  WM.  Vv 

KEEX,  M.D.,  LL.D.,  F.R.C.S.  (Hon.),  Professor  of  the  Principles  of  Surgery 
and    of   Clinical    Surgery,    Jefferson    Medical    College,    Philadelphia,    etc 
Octavo  volume  of  386  pages,  illustrated.  Published  i898          Cloth,  $3.00  net 

Dannreuther's  Minor  and  Emergency  Surgery 

Minor  and  Emergency  Surgery.  By  WALTER  T.  DANNKEITHER,  M.  D.,  Sur- 
geon to  St.  Elizabeth's  Hospital  and  to  St.  Bartholomew's  Clinic,  Xew  York 
City.  121110  of  225  pages,  illustrated.  Cloth,  $1.25  net.  Published  Oct.,  19U 

Bier's  Hyperemia  second  Edition,  June,  IQOQ 

Bier's  Hyperemic  Treatment  in  Surgery,  Medicine,  and  the  Specialties  : 
A  Manual  of  its  Practical  Application.  By  WILLY  MEYER,  M.  D.,  Professor 
of  Surgery  at  the  Xew  York  Post-Graduate  Medical  School  and  Hospital  ;  and 
PROF.  DR.  VICTOR  SCHMIEDEN,  Assistant  to  Prof.  Bier,  University  of  Berlin, 
Germany.  Octavo  of  280  pages,  with  original  illustrations.  Cloth,  53.00  net. 


Morris*  Dawn  of  the  Fourth  Era  in  Surgery 

Dawn  of  the  Fourth   Era  in  Surgery    and   Other    Articles.     By 

ROHERT  "I".    MORRIS,    M.  D.,   Xew  York   Post-Graduate   Medi;.al   School  and 
Hospital.       121110  of  145  pages,  illustrated.  August,  IQIO.  $1.25  nct- 


14  SJUVDEfiS'   BOOKS 


American  Illustrated  Dictionary  The  New  (9th)  Edition 

The  American  Illustrated  Medical  Dictionary.  With  tables 
of  Arteries,  Muscles,  Nerves,  Veins,  etc. ;  of  Bacilli,  Bacteria,  etc. ; 
Eponymic  Tables  of  Diseases,  Operations,  Stains,  Tests,  etc.  By  W.  A. 
NEWMAN  BORLAND,  M.D.  Large  octavo,  1179  pages.  Flexible  leather, 
$5.00  net;  with  thumb  index,  $5.50  net.  Published  October,  1917 

Howard  A.  Kelly,  M.D.,  Professor  of  Gynecology,  Johns  Hopkins  University,  Baltimore. 

"Dr.  Dorland's  dictionary  is  admirable.  It  is  so  well  gotten  up  and  of  such  con- 
venient size.  No  errors  have  been  found  in  my  use  of  it." 

Golebiewski  and  Bailey's  Accident  Diseases 

Atlas  and  Epitome  of  Diseases  Caused  by  Accidents.      By   DR. 

ED.  GOLEBIEWSKI,  of  Berlin.  Edited,  with  additions,  by  PEARCE  BAILEY, 
M.D.  Consulting  Neurologist  to  St.  Luke's  Hospital,  New  York  City. 
With  71  colored  figures  on  40  plates,  143  text-cuts,  and  549  pages  of 
text.  Cloth,  $4.00  net.  In  Saunders'  Hand-Atlas  Series.  Published  i<wx> 

Helferich  and  Bloodgood  on  Fractures 

Atlas  and  Epitome  of  Traumatic    Fractures  and  Dislocations 

By  PROF.  DR.  H.  HELFERICH,  of  Greifswald,  Prussia.  Edited,  with  ad- 
ditions, by  JOSEPH  C.  BLOODGOOD,  M.  D. ,  Associate  in  Surgery,  Johns 
Hopkins  University,  Baltimore.  216  colored  figures  on  64  lithographic 
plates,  190  text-cuts,  and  353  pages  of  text.  Cloth,  $3.00  net.  //;  Soun- 
ders' Atlas  Scries.  Published  June,  1902 

American  Pocket  Dictionary  New  (ioth)  Edition 

The  American  Pocket  Medical  Dictionary.  Edited  by  W.  A. 
NEWMAN  DORLAND,  A.  M.,  M.  D.,  Editor  "American  Illustrated  Med- 
ical Dictionary."  707  pages.  Full  leather,  limp,  with  gold  edges,  $1.25 
net:  with  patent  thumb  index,  $1.50  net.  Published  October,  1917 

Zuckerkandl  and  DaCosta's  Surgery  IdS 

Atlas  and  Epitome  of  Operative  Surgery.  By  DR.  O.  ZUCKER- 
KANDL, ot"  Vienna.  Edited,  with  additions,  by  J.  CHALMERS  DACOSTA, 
M.D.,  Samuel  D.  Gross  Professor  of  Surgery,  Jefferson  Medical  Col- 
lege, Philadelphia.  40  colored  plates,  278  text-cuts,  and  410  pages  of 
text.  Cloth,  $3.50  net.  In  Saunders"1  Atlas  Series.  Published  I^C.T 


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